@article {109706,
	title = {Hemoglobin Bohr Effects: Atomic Origin of the Histidine Residue Contributions},
	journal = {Biochemistry},
	volume = {52},
	year = {2013},
	pages = {8539-8555},
	abstract = {The Bohr effect in Hb, which refers to the dependence of the oxygen affinity on the pH, plays an important role in its cooperativity and physiol. function.  The dominant contribution to the Bohr effect arises from the difference in the pKa values of His residues of the unliganded (deoxy) and liganded (carbonmonoxy) structures.  Using recent high resoln. structures, the residue pKa values corresponding to the two structures are calcd.  The method is based on detg. the electrostatic interactions between residues in the protein, relative to those of the residue in soln., by use of the linearized finite difference Poisson-​Boltzmann equation and Monte Carlo sampling of protonation states.  Given that good agreement is obtained with the available exptl. values for the contribution of His residues in HbA to the Bohr effect, the calcd. results are used to det. the at. origin of the pKa shift between deoxy and carbonmonoxy HbA.  The contributions to the pKa shift calcd. by means of the linear response approxn. show that the salt bridge involving His146 plays an important role in the alk. Bohr effect, as suggested by Perutz but that other interactions are significant as well.  A corresponding anal. is made for the contribution of His143 to the acid Bohr effect for which there is no proposed explanation.  The method used is summarized and the program by which it is implemented is described in the Appendix.},
	author = {Guishan Zheng and Michael Schaefer and Martin Karplus}
}
@article {109421,
	title = {A Simplified Confinement Method for Calculating Absolute Free Energies and Free Energy and Entropy Differences},
	journal = {J. Phys. Chem. B},
	volume = {117},
	year = {2013},
	pages = {750-762},
	abstract = {A simple and robust formulation of the path-​independent confinement method for the calcn. of free energies is presented.  The simplified confinement method (SCM) does not require matrix diagonalization or switching off the mol. force field, and has a simple convergence criterion.  The method can be readily implemented in mol. dynamics programs with minimal or no code modifications.  Because the confinement method is a special case of thermodn. integration, it is trivially parallel over the integration variable.  The accuracy of the method is demonstrated using a model diat. mol., for which exact results can be computed anal.  The method is then applied to the alanine dipeptide in vacuum, and to the α-​helix <-> β-​sheet transition in a 16-​residue peptide modeled in implicit solvent.  The SCM requires less effort for the calcn. of free energy differences than previous formulations because it does not require computing normal modes.  The SCM has a diminished advantage for detg. abs. free energy values, because it requires decreasing the MD integration step to obtain accurate results.  An approx. confinement procedure is introduced, which can be used to est. directly the configurational entropy difference between two macrostates, without the need for addnl. computation of the difference in the free energy or enthalpy.  The approxn. has convergence properties similar to those of the std. confinement method for the calcn. of free energies.  The use of the approxn. requires about 5 times less wall-​clock simulation time than that needed to compute enthalpy differences to similar precision from an MD trajectory.  For the biomol. systems considered in this study, the errors in the entropy approxn. are under 10​\%.  Practical applications of the methods to proteins are currently limited to implicit solvent simulations.},
	author = {Victor Ovchinnikov and Marco Cecchini and Martin Karplus}
}
@article {109411,
	title = {A Gating Mechanism of Pentameric Ligand-​gated Ion Channels},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {110},
	year = {2013},
	pages = {E3987-E3996},
	abstract = {Pentameric ligand-​gated ion channels (pLGICs) play a central role in intercellular communication in the nervous system and are involved in fundamental processes such as attention, learning, and memory.  They are oligomeric protein assemblies that convert a chem. signal into an ion flux through the postsynaptic membrane, but the mol. mechanism of gating ions has remained elusive.  Here, we present atomistic mol. dynamics simulations of the prokaryotic channels from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC)​, whose crystal structures are thought to represent the active and the resting states of pLGICs, resp., and of the eukaryotic glutamate-​gated chloride channel from Caenorhabditis elegans (GluCI)​, whose openchannel structure was detd. complexed with the pos. allosteric modulator ivermectin.  Structural observables extd. from the trajectories of GLIC and ELIC are used as progress variables to analyze the time evolution of GluCI, which was simulated in the absence of ivermectin starting from the structure with bound ivermectin.  The trajectory of GluCI with ivermectin removed shows a sequence of structural events that couple agonist unbinding from the extracellular domain to ion-​pore closing in the transmembrane domain.  Based on these results, we propose a structural mechanism for the allosteric communication leading to deactivation​/activation of the GluCI channel.  This model of gating emphasizes the coupling between the quaternary twisting and the opening​/closing of the ion pore and is likely to apply to other members of the pLGIC family.},
	author = {Nicolas Calimet and Manuel Simoes and Jean-Pierre Changeux and Martin Karplus and Antoine Taly and Marco Cecchini}
}
@article {109406,
	title = {New Insights into the Folding of a β-​Sheet Miniprotein in a Reduced Space of Collective Hydrogen Bond Variables: Application to a Hydrodynamic Analysis of the Folding Flow},
	journal = {J. Phys. Chem. B},
	volume = {117},
	year = {2013},
	pages = {6092-6105},
	abstract = {A new anal. of the 20 μs equil. folding​/unfolding mol. dynamics simulations of the three-​stranded antiparallel β-​sheet miniprotein (beta3s) in implicit solvent is presented.  The conformation space is reduced in dimensionality by introduction of linear combinations of hydrogen bond distances as the collective variables making use of a specially adapted principal component anal. (PCA)​; i.e., to make structured conformations more pronounced, only the formed bonds are included in detg. the principal components.  A three-​dimensional (3D) subspace gives a meaningful representation of the folding behavior.  The first component, to which eight native hydrogen bonds make the major contribution (four in each beta hairpin)​, is found to play the role of the reaction coordinate for the overall folding process, while the second and third components distinguish the structured conformations.  The representative points of the trajectory in the 3D space are grouped into conformational clusters that correspond to locally stable conformations of beta3s identified in earlier work.  A simplified kinetic network based on the three components is constructed, and it is complemented by a hydrodynamic anal.  The latter, making use of passive tracers in 3D space, indicates that the folding flow is much more complex than suggested by the kinetic network.  A 2D representation of streamlines shows there are vortexes which correspond to repeated local rearrangement, not only around min. of the free energy surface but also in flat regions between min.  The vortexes revealed by the hydrodynamic anal. are apparently not evident in folding pathways generated by transition-​path sampling.  Making use of the fact that the values of the collective hydrogen bond variables are linearly related to the Cartesian coordinate space, the RMSD between clusters is detd.  The transition rates show an approx. exponential correlation with distance in the hydrogen bond subspace.  Comparison with the many published studies shows good agreement with the present anal. for the parts that can be compared, supporting the robust character of the authors{\textquoteright} understanding of this hydrogen atom of protein folding.},
	author = {Igor V. Kalgin and Amedeo Caflisch and Sergei F. Chekmarev and Martin Karplus}
}
@article {109471,
	title = {Strandwise translocation of a DNA glycosylase on undamaged DNA},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {109},
	year = {2012},
	pages = {1086-1091},
	abstract = {Base excision repair of genotoxic nucleobase lesions in the genome is critically dependent upon the ability of DNA glycosylases to locate rare sites of damage embedded in a vast excess of undamaged DNA, using only thermal energy to fuel the search process.  Considerable interest surrounds the question of how DNA glycosylases translocate efficiently along DNA while maintaining their vigilance for target damaged sites.  Here, we report the observation of strandwise translocation of 8-​oxoguanine DNA glycosylase, MutM, along undamaged DNA.  In these complexes, the protein is obsd. to translocate by one nucleotide on one strand while remaining untranslocated on the complementary strand.  We further report that alterations of single base-​pairs or a single amino acid substitution (R112A) can induce strandwise translocation.  Mol. dynamics simulations confirm that MutM can translocate along DNA in a strandwise fashion.  These observations reveal a previously unobserved mode of movement for a DNA-​binding protein along the surface of DNA.},
	author = {Yan Qi and Kwangho Nam and Marie C. Spong and Anirban Banerjee and Rou-Jia Sung and Michael Zhang and Martin Karplus and Verdine, Gregory L.}
}
@article {109466,
	title = {Analysis and Elimination of a Bias in Targeted Molecular Dynamics Simulations of Conformational Transitions: Application to Calmodulin},
	journal = {J. Phys. Chem. B},
	volume = {116},
	year = {2012},
	pages = {8584-8603},
	abstract = {The popular targeted mol. dynamics (TMD) method for generating transition paths in complex biomol. systems is revisited.  In a typical TMD transition path, the large-​scale changes occur early and the small-​scale changes tend to occur later.  As a result, the order of events in the computed paths depends on the direction in which the simulations are performed.  To identify the origin of this bias, and to propose a method in which the bias is absent, variants of TMD in the restraint formulation are introduced and applied to the complex open <-> closed transition in the protein calmodulin.  Due to the global best-​fit rotation that is typically part of the TMD method, the simulated system is guided implicitly along the lowest-​frequency normal modes, until the large spatial scales assocd. with these modes are near the target conformation.  The remaining portion of the transition is described progressively by higher-​frequency modes, which correspond to smaller-​scale rearrangements.  A straightforward modification of TMD that avoids the global best-​fit rotation is the locally restrained TMD (LRTMD) method, in which the biasing potential is constructed from a no. of TMD potentials, each acting on a small connected portion of the protein sequence.  With a uniform distribution of these elements, transition paths that lack the length-​scale bias are obtained.  Trajectories generated by steered MD in dihedral angle space (DSMD)​, a method that avoids best-​fit rotations altogether, also lack the length-​scale bias.  To examine the importance of the paths generated by TMD, LRTMD, and DSMD in the actual transition, we use the finite-​temp. string method to compute the free energy profile assocd. with a transition tube around a path generated by each algorithm.  The free energy barriers assocd. with the paths are comparable, suggesting that transitions can occur along each route with similar probabilities.  This result indicates that a broad ensemble of paths needs to be calcd. to obtain a full description of conformational changes in biomols.  The breadth of the contributing ensemble suggests that energetic barriers for conformational transitions in proteins are offset by entropic contributions that arise from a large no. of possible paths.},
	author = {Victor Ovchinnikov and Martin Karplus}
}
@article {109451,
	title = {Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors},
	journal = {Chemistry - A European Journal},
	volume = {18},
	year = {2012},
	pages = {8978-8986},
	abstract = {A concise and modular synthesis of pochonin E and F, and their epimers at C-​6 established the correct stereochem. of these two natural products to be (6R)​.  Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90)​, which has been the focus of intense drug discovery efforts.  Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C-​6 position.  Mol. dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.},
	author = {Ganesan Karthikeyan and Claudio Zambaldo and Sofia Barluenga and Vincent Zoete and Martin Karplus and Nicolas Winssinger}
}
@article {109441,
	title = {Enforced Presentation of an Extrahelical Guanine to the Lesion Recognition Pocket of Human 8-​Oxoguanine Glycosylase, hOGG1},
	journal = {Journal of Biological Chemistry},
	volume = {287},
	year = {2012},
	pages = {24916-24928},
	abstract = {A poorly understood aspect of DNA repair proteins is their ability to identify exceedingly rare sites of damage embedded in a large excess of nearly identical undamaged DNA, while catalyzing repair only at the damaged sites.  Progress toward understanding this problem has been made by comparing the structures and biochem. behavior of these enzymes when they are presented with either a target lesion or a corresponding undamaged nucleobase.  Trapping and analyzing such DNA-​protein complexes is particularly difficult in the case of base extrusion DNA repair proteins because of the complexity of the repair reaction, which involves extrusion of the target base from DNA followed by its insertion into the active site where glycosidic bond cleavage is catalyzed.  Here we report the structure of a human 8-​oxoguanine (oxoG) DNA glycosylase, hOGG1, in which a normal guanine from DNA has been forcibly inserted into the enzyme active site.  Although the interactions of the nucleobase with the active site are only subtly different for G vs. oxoG, hOGG1 fails to catalyze excision of the normal nucleobase.  This study demonstrates that even if hOGG1 mistakenly inserts a normal base into its active site, the enzyme can still reject it on the basis of catalytic incompatibility.},
	author = {Charisse M. Crenshaw and Kwangho Nam and Kimberly Oo and Peter S. Kutchukian and Brian R. Bowman and Martin Karplus and Verdine, Gregory L.}
}
@article {109746,
	title = {Free energy of conformational transition paths in biomolecules: The string method and its application to myosin VI},
	journal = {J. Chem. Phys.},
	volume = {134},
	year = {2011},
	pages = {085103/1-085103/25},
	abstract = {A set of techniques developed under the umbrella of the string method is used in combination with all-​atom mol. dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI.  The challenges specific to the application of these techniques to such a large and complex biomol. are addressed in detail.  These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition.  A detailed description of the PPS<->R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion.  The methodol. developed here is expected to be useful more generally in studies of conformational transitions in complex biomols.  (c) 2011 American Institute of Physics.},
	author = {Victor Ovchinnikov and Martin Karplus and Eric Vanden-Eijnden}
}
@article {109741,
	title = {Unsuspected pathway of the allosteric transition in hemoglobin},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {108},
	year = {2011},
	pages = {5608-5613},
	abstract = {Large conformational transitions play an essential role in the function of many proteins, but expts. do not provide the at. details of the path followed in going from one end structure to the other.  For the Hb tetramer, the transition path between the unliganded (T) and tetraoxygenated (R) structures is not known, which limits our understanding of the cooperative mechanism in this classic allosteric system, where both tertiary and quaternary changes are involved.  The conjugate peak refinement algorithm is used to compute an unbiased min. energy path at at. detail between the two end states.  Although the results confirm some of the proposals of Perutz, the subunit motions do not follow the textbook description of a simple rotation of one αβ-​dimer relative to the other.  Instead, the path consists of two sequential quaternary rotations, each involving different subdomains and axes.  The quaternary transitions are preceded and followed by phases of tertiary structural changes.  The results explain the recent photodissocn. measurements, which suggest that the quaternary transition has a fast (2 μs) as well as a slow (20 μs) component and provide a testable model for single mol. FRET expts.},
	author = {Stefan Fischer and Kenneth W. Olsen and Kwangho Nam and Martin Karplus}
}
@article {109736,
	title = {Determining the Conformational Change that Accompanies Donor-​Acceptor Distance Fluctuations: An Umbrella Sampling Analysis},
	journal = {J. Phys. Chem. B},
	volume = {115},
	year = {2011},
	pages = {7991-7995},
	abstract = {The response of a protein to variation of a specific coordinate can provide insights into the role of the overall architecture in the structural change.  Given that the calcd. potential of mean force governing the fluctuation of an electron transfer donor-​acceptor distance in the NAD(P)​H:flavin oxidoreductase (Fre)​/FAD complex was shown to agree with expt., an anal. of the structural response of the rest of the protein to that distance change was made.  Significant displacements are found throughout much of the protein, and the coupling pathway resulting in the structural changes was detd.  A covariance anal. based on the quasiharmonic modes of the unperturbed protein was used to provide information concerning how the residue motions are correlated.  It is found that of the three regions identified as moving together in an NMR study, two undergo significant structural changes when the electron donor-​acceptor distance is varied, and the third does not.},
	author = {Guo-Bin Luo and Martin Karplus}
}
@article {109731,
	title = {Behind the folding funnel diagram},
	journal = {Nature Chemical Biology},
	volume = {7},
	year = {2011},
	pages = {401-404},
	abstract = {A review.  This Commentary clarifies the meaning of the funnel diagram, which has been widely cited in papers on protein folding.  To aid in the anal. of the funnel diagram, this Commentary reviews historical approaches to understanding the mechanism of protein folding.  The primary role of free energy in protein folding is discussed, and it is pointed out that the increase in the configurational entropy as the native state is approached hinders folding, rather than guiding it.  Diagrams are introduced that provide a less ambiguous representation of the factors governing the protein folding reaction than the funnel diagram.},
	author = {Martin Karplus}
}
@article {109721,
	title = {Lagrangian formulation with dissipation of Born-​Oppenheimer molecular dynamics using the density-​functional tight-​binding method},
	journal = {J. Chem. Phys.},
	volume = {135},
	year = {2011},
	pages = {044122/1-044122/17},
	abstract = {An important element detg. the time requirements of Born-​Oppenheimer mol. dynamics (BOMD) is the convergence rate of the self-​consistent soln. of Roothaan equations (SCF)​.  We show here that improved convergence and dynamics stability can be achieved by use of a Lagrangian formalism of BOMD with dissipation (DXL-​BOMD)​.  In the DXL-​BOMD algorithm, an auxiliary electronic variable (e.g., the electron d. or Fock matrix) is propagated and a dissipative force is added in the propagation to maintain the stability of the dynamics.  Implementation of the approach in the self-​consistent charge d. functional tight-​binding method makes possible simulations that are several hundred picoseconds in lengths, in contrast to earlier DFT-​based BOMD calcns., which have been limited to tens of picoseconds or less.  The increase in the simulation time results in a more meaningful evaluation of the DXL-​BOMD method.  A comparison is made of the no. of iterations (and time) required for convergence of the SCF with DXL-​BOMD and a std. method (starting with a zero charge guess for all atoms at each step)​, which gives accurate propagation with reasonable SCF convergence criteria.  From tests using NVE simulations of C2F4 and 20 neutral amino acid mols. in the gas phase, it is found that DXL-​BOMD can improve SCF convergence by up to a factor of two over the std. method.  Corresponding results are obtained in simulations of 32 water mols. in a periodic box.  Linear response theory is used to analyze the relationship between the energy drift and the correlation of geometry propagation errors. },
	author = {Guishan Zheng and Anders M. N. Niklasson and Martin Karplus}
}
@article {109716,
	title = {A Conformational Transition in the Myosin VI Converter Contributes to the Variable Step Size},
	journal = {Biophysical Journal},
	volume = {101},
	year = {2011},
	pages = {2436-2444},
	abstract = {Myosin VI (MVI) is a dimeric mol. motor that translocates backwards on actin filaments with a surprisingly large and variable step size, given its short lever arm.  A recent x-​ray structure of MVI indicates that the large step size can be explained in part by a novel conformation of the converter subdomain in the prepowerstroke state, in which a 53-​residue insert, unique to MVI, reorients the lever arm nearly parallel to the actin filament.  To det. whether the existence of the novel converter conformation could contribute to the step-​size variability, we used a path-​based free-​energy simulation tool, the string method, to show that there is a small free-​energy difference between the novel converter conformation and the conventional conformation found in other myosins.  This result suggests that MVI can bind to actin with the converter in either conformation.  Models of MVI​/MV chimeric dimers show that the variability in the tilting angle of the lever arm that results from the two converter conformations can lead to step-​size variations of \~{}12 nm.  These variations, in combination with other proposed mechanisms, could explain the exptl. detd. step-​size variability of \~{}25 nm for wild-​type MVI.  Mutations to test the findings by expt. are suggested.},
	author = {Victor Ovchinnikov and Marco Cecchini and Eric Vanden-Eijnden and Martin Karplus}
}
@article {110036,
	title = {Entrapment and Structure of an Extrahelical Guanine Attempting to Enter the Active Site of a Bacterial DNA Glycosylase, MutM},
	journal = {Journal of Biological Chemistry},
	volume = {285},
	year = {2010},
	pages = {1468-1478},
	abstract = {MutM, a bacterial DNA glycosylase, protects genome integrity by catalyzing glycosidic bond cleavage of 8-​oxoguanine (oxoG) lesions, thereby initiating base excision DNA repair.  The process of searching for and locating oxoG lesions is esp. challenging, because of the close structural resemblance of oxoG to its million-​fold more abundant progenitor, G.  Extrusion of the target nucleobase from the DNA double helix to an extrahelical position is an essential step in lesion recognition and catalysis by MutM.  Although the interactions between the extruded oxoG and the active site of MutM have been well characterized, little is known in structural detail regarding the interrogation of extruded normal DNA bases by MutM.  Here we report the capture and structural elucidation of a complex in which MutM is attempting to present an undamaged G to its active site.  The structure of this MutM-​extrahelical G complex provides insights into the mechanism MutM employs to discriminate against extrahelical normal DNA bases and into the base extrusion process in general.},
	author = {Yan Qi and Marie C. Spong and Kwangho Nam and Martin Karplus and Verdine, Gregory L.}
}
@article {110021,
	title = {The Mechanism of the Translocation Step in DNA Replication by DNA Polymerase I: A Computer Simulation Analysis},
	journal = {Structure},
	volume = {18},
	year = {2010},
	pages = {83-93},
	abstract = {High-​fidelity DNA polymerases copy DNA rapidly and accurately by adding correct deoxynucleotide triphosphates to a growing primer strand of DNA.  Following nucleotide incorporation, a series of conformational changes translocate the DNA substrate by one base pair step, readying the polymerase for the next round of incorporation.  Mol. dynamics simulations indicate that the translocation consists globally of a polymerase fingers-​opening transition, followed by the DNA displacement and the insertion of the template base into the preinsertion site.  They also show that the pyrophosphate release facilitates the opening transition and that the universally conserved Y714 plays a key role in coupling polymerase opening to DNA translocation.  The transition involves several metastable intermediates in one of which the O helix is bent in the vicinity of G711.  Completion of the translocation appears to require a gating motion of the O1 helix, perhaps facilitated by the presence of G715.  These roles are consistent with the high level of conservation of Y714 and the two glycine residues at these positions.  It is likely that a corresponding mechanism is applicable to other polymerases.},
	author = {Andrei A. Golosov and Joshua J. Warren and Lorena S. Beese and Martin Karplus}
}
@article {110011,
	title = {Mechanical Coupling in Myosin V: A Simulation Study},
	journal = {Journal of Molecular Biology},
	volume = {395},
	year = {2010},
	pages = {815-833},
	abstract = {Myosin motor function depends on the interaction between different domains that transmit information from one part of the mol. to another.  The interdomain coupling in myosin V is studied with restrained targeted mol. dynamics (MD) using an all-​atom representation in explicit solvent.  To elucidate the origin of the conformational change due to the binding of ATP, targeting forces are applied to small sets of atoms (the forcing sets, FSs) in the direction of their displacement from the rigor conformation, which has a closed actin-​binding cleft, to the post-​rigor conformation, in which the cleft is open.  The "minimal" FS that results in extensive structural changes in the overall myosin conformation is composed of ATP, switch 1, and the nearby HF, HG, and HH helixes.  Addn. of switch 2 to the FS is required to achieve a complete opening of the actin-​binding cleft.  The restrained targeted mol. dynamics simulations reveal the mech. coupling pathways between (i) the nucleotide-​binding pocket (NBP) and the actin-​binding cleft, (ii) the NBP and the converter, and (iii) the actin-​binding cleft and the converter.  Closing of the NBP due to ATP binding is tightly coupled to the opening of the cleft and leads to the rupture of a key hydrogen bond (F441N​/A684O) between switch 2 and the SH1 helix.  The actin-​binding cleft may mediate the rupture of this bond via a connection between the HW helix, the relay helix, and switch 2.  The findings are consistent with exptl. studies and a recent normal mode anal.  The present method is expected to be useful more generally in studies of interdomain coupling in proteins.},
	author = {Victor Ovchinnikov and Bernhardt L. Trout and Martin Karplus}
}
@article {110001,
	title = {Dynamical aspects of molecular recognition},
	journal = {Journal of Molecular Recognition},
	volume = {23},
	year = {2010},
	pages = {102-104},
	author = {Martin Karplus}
}
@article {109996,
	title = {PR65, the HEAT-​repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {107},
	year = {2010},
	pages = {2467-2472},
	abstract = {PR65 is the two-​layered (α-​α solenoid) HEAT-​repeat scaffold of protein phosphatase PP2A.  Mol. dynamics (MD) simulations predict that at forces expected in living systems, PR65 undergoes (visco-​)​elastic deformations in response to pulling​/pushing on its ends.  At lower forces, smooth global flexural and torsional changes occur via even redistribution of stress along the hydrophobic core of the mol.  At intermediate forces, helix-​helix sepn. along one layer ("fracturing") leads to global relaxation plus loss of contact in the other layer to unstack the affected units.  Fracture sites are detd. by unusual sequences in contiguous interhelix turns.  Normal mode anal. of the heterotrimeric PP2A enzyme reveals that its ambient conformational fluctuations are dominated by elastic deformations of PR65, which introduce a mech. linkage between the sep. bound regulatory and catalytic subunits.  PR65-​dominated fluctuations of PP2A have the effect of opening and closing the enzyme{\textquoteright}s substrate binding​/catalysis interface, as well as altering the positions of certain catalytic residues.  These results suggest that substrate binding​/catalysis are sensitive to mech. force.  Force could be imposed from the outside (e.g., in PP2A{\textquoteright}s response to spindle tension) or arise spontaneously (e.g., in PP2A{\textquoteright}s interaction with unstructured proteins such as Tau, a microtubule-​assocd. Alzheimer{\textquoteright}s-​implicated protein)​.  The present example supports the view that conformation and function of protein complexes can be modulated by mech. energy inputs, as well as by chem. energy inputs from ligand binding.  Given that helical-​repeat proteins are involved in many cellular processes, the findings also encourage the view that mech. forces may be of widespread importance.},
	author = {Alison Grinthal and Ivana Adamovic and Beth Weiner and Martin Karplus and Nancy Kleckner}
}
@article {109991,
	title = {Pi release from myosin: A simulation analysis of possible pathways},
	journal = {Structure},
	volume = {18},
	year = {2010},
	pages = {458-470},
	abstract = {The release of inorg. phosphate (Pi) is an important element in actomyosin function and has been shown to be accelerated by the binding of myosin to actin.  To provide information about the structural elements important for Pi release, possible escape pathways from various isolated myosin II structures were detd. by mol. dynamics simulations designed for studying such slow processes.  The residues forming the pathways were identified and their role was evaluated by mutant simulations.  Pi release was slow in the pre-​powerstroke structure, an important element in preventing the powerstroke prior to actin binding, and was much more rapid for Pi modeled into the post-​rigor and rigor-​like structures.  The previously proposed backdoor route was dominant in the pre-​powerstroke and post-​rigor states, whereas a different path was most important in the rigor-​like state.  This finding suggested a mechanism for the actin-​activated acceleration of Pi release.},
	author = {Marco Cecchini and Yuri Alexeev and Martin Karplus}
}
@article {109971,
	title = {Protein dynamics investigated by inherent structure analysis},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {107},
	year = {2010},
	pages = {9152-9157},
	abstract = {Mol. dynamics (MD) simulations provide essential information about the thermodn. and dynamics of proteins.  To construct the free-​energy surface from equil. trajectories, it is necessary to group the individual snapshots in a meaningful way.  The inherent structures (IS) are shown to provide an appropriate discretization of the trajectory and to avoid problems that can arise in clustering algorithms that have been employed previously.  The IS-​based approach is illustrated with a 30-​ns room temp. "native" state MD simulation of a 10-​residue peptide in a β-​hairpin conformation.  The transitions between the IS are used to construct a configuration space network from which a one-​dimensional free-​energy profile is obtained with the mincut method.  The results demonstrate that the IS approach is useful and that even for this simple system, there exists a nontrivial organization of the native state into several valleys sepd. by barriers as high as 3 kcal​/mol.  Further, by introducing a coarse-​grained network, it is demonstrated that there are multiple pathways connecting the valleys.  This scenario is hidden when the snapshots of the trajectory are used directly with rmsd clustering to compute the free-​energy profile.  Application of the IS approach to the native state of the PDZ2 signaling domain indicates its utility for the study of biol. relevant systems.},
	author = {Francesco Rao and Martin Karplus}
}
@article {109966,
	title = {Conformational Free-​Energy Difference of a Miniprotein from Nonequilibrium Simulations},
	journal = {Journal of Physical Chemistry Letters},
	volume = {1},
	year = {2010},
	pages = {1922-1926},
	abstract = {Conformational free-​energy differences are essential thermodn. quantities for understanding the function of many biomols.  They are accessible from computer simulations, but their accurate calcn. is a challenging task.  Here nonequil. computer simulations and the differential fluctuation theorem are used to evaluate the free-​energy difference between two conformational states of a structured miniprotein, the β-​hairpin of protein G, with an implicit treatment of the solvent.  A mol. dynamics-​based protocol is employed for the simulation of rapid switches between the conformational states in both the forward and the reverse direction.  From the work performed on the system in the individual switches, the conformational free-​energy difference is detd. by use of the differential fluctuation theorem.  The results are in excellent agreement with ref. calcns. from a long mol. dynamics simulation and from the confinement method.  The nonequil. approach is a computationally efficient method for the calcn. of conformational free-​energy differences for biol. systems.},
	author = {Martin Spichty and Marco Cecchini and Martin Karplus}
}
@inbook {109956,
	title = { How biomolecular motors work: synergy between single molecule experiments and single molecule simulations },
	booktitle = {Single Molecule Spectroscopy in Chemistry, Physics and Biology},
	volume = {96},
	year = {2010},
	pages = {3-22},
	publisher = {Springer Series in Chemical Physics},
	organization = {Springer Series in Chemical Physics},
	address = {Berlin Heidelberg},
	abstract = {A review.  Cells are a collection of machines with a wide range of functions.  Most of these machines are proteins.  To understand their mechanisms, a synergistic combination of expts. and computer simulations is required.  Some underlying concepts concerning proteins involved in such machines and their motions are presented.  An essential element is that the conformational changes required for machine function are built into the structure by evolution.  Specific biomol. motors (kinesin and F1-​ATPase) are considered and how they work is described.},
	author = {Martin Karplus and Jingzhi Pu}
}
@article {110586,
	title = {Signaling pathways of PDZ2 domain: a molecular dynamics interaction correlation analysis},
	journal = {Proteins: Structure, Function \& Genetics},
	volume = {74},
	year = {2009},
	pages = {145-154},
	abstract = {PDZ domains are found in many signaling proteins.  One of their functions is to provide scaffolds for forming membrane-​assocd. protein complexes by binding to the carboxyl termini of their partners.  PDZ domains are thought also to play a signal transduction role by propagating the information that binding has occurred to remote sites.  In this study, a mol. dynamics (MD) simulation-​based approach, referred to as an interaction correlation anal., is applied to the PDZ2 domain to identify the possible signal transduction pathways.  A residue correlation matrix is constructed from the interaction energy correlations between all residue pairs obtained from the MD simulations.  Two continuous interaction pathways, starting at the ligand binding pocket, are identified by a hierarchical clustering anal. of the residue correlation matrix.  One pathway is mainly localized at the N-​terminal side of helix α1 and the adjacent C-​terminus of loop β1-​β2.  The other pathway is perpendicular to the central β-​sheet and extends toward the side of PDZ2 domain opposite to the ligand binding pocket.  The results complement previous studies based on multiple sequence anal., NMR, and MD simulations.  Importantly, they reveal the energetic origin of the long-​range coupling.  The PDZ2 results, as well as the earlier rhodopsin anal., show that the interaction correlation anal. is a robust approach for detg. pathways of intramol. signal transduction.},
	author = {Yifei Kong and Martin Karplus}
}
@article {110581,
	title = {Gaussian-​Mixture Umbrella Sampling},
	journal = {J. Phys. Chem. B},
	volume = {113},
	year = {2009},
	pages = {4664-4673},
	abstract = {We introduce the Gaussian-​mixt. umbrella sampling method (GAMUS)​, a biased mol. dynamics technique based on adaptive umbrella sampling that efficiently escapes free energy min. in multidimensional problems.  The prior simulation data are reweighted with a max. likelihood formulation, and the new approx. probability d. is fit to a Gaussian-​mixt. model, augmented by information about the unsampled areas.  The method can be used to identify free energy min. in multidimensional reaction coordinates.  To illustrate GAMUS, we apply it to the alanine dipeptide (2D reaction coordinate) and tripeptide (4D reaction coordinate)​.},
	author = {Paul Maragakis and Arjan van der Vaart and Martin Karplus}
}
@article {110556,
	title = {CHARMM: The biomolecular simulation program},
	journal = {Journal of Computational Chemistry},
	volume = {30},
	year = {2009},
	pages = {1545-1614},
	abstract = {A review.  CHARMM (Chem. at HARvard Mol. Mechanics) is a highly versatile and widely used mol. simulation program.  It has been developed over the last three decades with a primary focus on mols. of biol. interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small mol. ligands, as they occur in soln., crystals, and membrane environments.  For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, mol. minimization, dynamics, and anal. techniques, and model-​building capabilities.  The CHARMM program is applicable to problems involving a much broader class of many-​particle systems.  Calcns. with CHARMM can be performed using a no. of different energy functions and models, from mixed quantum mech.-​mol. mech. force fields, to all-​atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models.  The program has been ported to numerous platforms in both serial and parallel architectures.  This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. },
	author = {Bernard R. Brooks and Charles L. Brooks and Alexander D. Mackerell and Lennart Nilsson and Robert J. Petrella and Benoit Roux and Youngdo Won and Georgios Archontis and Christian Bartels and Stefan Boresch and Amedeo Caflisch and Leo Caves and Qiang Cui and Aaron R. Dinner and Michael Feig and Stefan Fischer and Jiali Gao and Milan Hodoscek and Wonpil Im and Krzysztof Kuczera and Themis Lazaridis and Jianpeng Ma and Victor Ovchinnikov and Emanuele Paci and Richard W. Pastor and Carol B. Post and Jingzhi Pu and Michael Schaefer and Bruce Tidor and Richard M. Venable and H. Lee Woodcock and Xiongwu Wu and Wei Yang and Darrin M. York and Martin Karplus}
}
@article {110541,
	title = {The HSP90 binding mode of a radicicol-​like E-​oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts},
	journal = {Biophys. Chem.},
	volume = {143},
	year = {2009},
	pages = {111-123},
	abstract = {We det. the binding mode of a macrocyclic radicicol-​like oxime to yeast HSP90 by combining computer simulations and exptl. measurements.  We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90.  Docking poses are then evaluated by the use of binding free energy estns. with the linear interaction energy method.  Comparison of QM​/MM-​calcd. NMR chem. shifts with exptl. shift data for a selective subset of backbone 15N provides an addnl. evaluation criteria.  As a final test we check the binding modes against available structure-​activity-​relationships.  We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol-​HSP90 complex.},
	author = {Martin Spichty and Antoine Taly and Franz Hagn and Horst Kessler and Sofia Barluenga and Nicolas Winssinger and Martin Karplus}
}
@article {110411,
	title = {Folding of a SH3 Domain: Standard and "Hydrodynamic" Analyses},
	journal = {J. Phys. Chem. B},
	volume = {113},
	year = {2009},
	pages = {12759-12772},
	abstract = {Discrete mol. dynamics has been used to study the folding of a SH3 domain with a Cα-​based Go-​model at a temp. within the native state stability region.  A std. anal. of the folding process, based on consideration of the mean-​force (free energy) surfaces, contact maps and folding time distributions, is complemented by a "hydrodynamic" Chekmarev{\textquoteright}s description of folding flows using two and three collective variables.  Two types of folding trajectories (fast and slow) follow essentially different routes in the final stage of folding.  The hydrodynamic description makes possible the calcn. of folding flows corresponding to these routes.  The results show that the probability flows do not correspond to the free energy surface and that vortex formation is involved in the slow trajectories.  Comparison of the simulation results with the exptl. data suggests that the two-​state kinetics obsd. for Fyn and Src SH3 domain folding are assocd. with the slow trajectories, in which a partly formed N- and C-​terminal β sheet hinders the RT-​loop from attaching to the protein core; the fast trajectories are not obsd. because they are in the dead time (1 ms) of the expts.},
	author = {Igor V. Kalgin and Martin Karplus and Sergei F. Chekmarev}
}
@article {110406,
	title = {Segmented Transition Pathway of the Signaling Protein Nitrogen Regulatory Protein C},
	journal = {Journal of Molecular Biology},
	volume = {392},
	year = {2009},
	pages = {823-836},
	abstract = {Recent advances in exptl. methods provide increasing evidence that proteins sample the conformational substates that are important for function in the absence of their ligands.  An example is the receiver domain of nitrogen regulatory protein C (NtrC)​, a member of the phosphorylation-​mediated signaling family of "two-​component systems.".  The receiver domain of nitrogen regulatory protein C (NtrCR) samples both inactive conformation and the active conformation before phosphorylation.  Here we det. a possible pathway of interconversion between the active state and the inactive state by targeted mol. dynamics (TMD) simulations and quasi-​harmonic anal. (QHA)​; these methods are used because the exptl. conversion rate is in the high microsecond range, longer than those that are easily accessible to atomistic mol. dynamics simulations.  The calcd. pathway is found to be composed of four consecutive stages described by different progress variables.  The lowest quasi-​harmonic principal components from unbiased mol. dynamics simulations on the active state correspond to the first stage, but not to the subsequent stages of the transition.  The targeted mol. dynamics pathway suggests that several transient nonnative hydrogen bonds may facilitate the transition.},
	author = {Ming Lei and Janice Velos and Alexandra Gardino and Alexsandr Kivenson and Martin Karplus and Dorothee Kern}
}
@article {110346,
	title = {Analysis of an Anomalous Mutant of MutM DNA Glycosylase Leads to New Insights into the Catalytic Mechanism},
	journal = {J. Am. Chem. Soc.},
	volume = {131},
	year = {2009},
	pages = {18208-18209},
	abstract = {Lesion-​specific DNA glycosylases play the key role in base-​excision DNA repair finding the damaged base and catalyzing its removal.  Structural, computational, and exptl. studies have shown that MutM, a bacterial DNA glycosylase specific for 8-​oxoguanine (oxoG)​, encounters for oxoG lesion.  The damaged nucleobase is extruded from the DNA and inserted into the enzyme active site, whereupon catalysis of glycosidic bond cleavage ensues.  Here we show that the E3Q mutation provides substantial stabilization of oxoG in the active site of MutM.  The simulations further show that oxoG is stabilized in the active site by protonation of the E3 carboxy group during the insertion process.  It is also pointed out that the protonation could be significant for base-​excision catalysis.  The results highlight the importance of accounting for the potential energetic and structural effects of mutations frequently introduced into enzymes to capture otherwise fleeting intermediates.},
	author = {Kwangho Nam and Verdine, Gregory L. and Martin Karplus}
}
@article {110336,
	title = {Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme},
	journal = {Nature },
	volume = {462},
	year = {2009},
	pages = {762-766},
	abstract = {How living systems detect the presence of genotoxic damage embedded in a million-​fold excess of undamaged DNA is an unresolved question in biol.  Here we have captured and structurally elucidated a base-​excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-​oxoguanine (oxoG)​, nested within a DNA duplex.  Three structures of intrahelical oxoG-​encounter complexes are compared with sequence-​matched structures contg. a normal G base in place of an oxoG lesion.  Although the protein-​DNA interfaces in the matched complexes differ by only two atoms-​those that distinguish oxoG from G-​their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter.  All-​atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the crit. free energy difference between oxoG and G along the extrusion pathway.},
	author = {Yan Qi and Marie C. Spong and Kwangho Nam and Anirban Banerjee and Sao Jiralerspong and Martin Karplus and Verdine, Gregory L.}
}
@article {109981,
	title = {Calculation of Free-​Energy Differences by Confinement Simulations. Application to Peptide Conformers},
	journal = {J. Phys. Chem. B},
	volume = {113},
	year = {2009},
	pages = {9728-9740},
	abstract = {Conformational free-​energy differences are key quantities for understanding important phenomena in mol. biol. that involve large structural changes of macromols.  In this paper, an improved version of the confinement approach, which is based on earlier developments, is used to det. the free energy of individual mol. states by progressively restraining the corresponding mol. structures to pure harmonic basins, whose abs. free energy can be computed by normal-​mode anal.  The method is used to calc. the free-​energy difference between two conformational states of the alanine dipeptide in vacuo, and of the β-​hairpin from protein G with an implicit solvation model.  In all cases, the confinement results are in excellent agreement with the ones obtained from converged equil. mol. dynamics simulations, which have a much larger computational cost.  The systematic and statistical errors of the results are evaluated and the origin of the errors is identified.  The sensitivity of the calcd. free-​energy differences to structure-​based definitions of the mol. states is discussed.  A variant of the method, which closes the thermodn. cycle by a quasi-​harmonic rather than harmonic anal., is introduced.  The latter is proposed for possible use with explicit solvent simulations.},
	author = {Marco Cecchini and Sergei V. Krivov and Martin Spichty and Martin Karplus}
}
@article {113111,
	title = {Force Generation in Kinesin Hinges on Cover-​Neck Bundle Formation},
	journal = {Structure},
	volume = {16},
	year = {2008},
	pages = {62-71},
	abstract = {Summary: In kinesin motors, a fundamental question concerns the mechanism by which ATP binding generates the force required for walking.  Anal. of available structures combined with mol. dynamics simulations demonstrates that the conformational change of the neck linker involves the nine-​residue-​long N-​terminal region, the cover strand, as an element that is essential for force generation.  Upon ATP binding, it forms a β sheet with the neck linker, the cover-​neck bundle, which induces the forward motion of the neck linker, followed by a latch-​type binding to the motor head.  The estd. stall force and anisotropic response to external loads calcd. from the model agree with force-​clamp measurements.  The proposed mechanism for force generation by the cover-​neck bundle formation appears to apply to several kinesin families.  It also elucidates the design principle of kinesin as the smallest known processive motor.},
	author = {Wonmuk Hwang and Matthew J. Lang and Martin Karplus}
}
@article {113106,
	title = {Hydrodynamic description of protein folding},
	journal = {Phys. Rev. Lett.},
	volume = {100},
	year = {2008},
	pages = {018107/1-018107/4},
	abstract = {A hydrodynamic description of protein folding is proposed and illustrated with a lattice protein model, which has a free energy surface (FES) typical of proteins with 2-​state folding kinetics.  The flows from the unfolded to the native state are concd. in a limited region of the FES.  The rest is occupied by a flow "vortex", which does not lead to the native state.  In contrast, with intermediates that are assocd. with local min., the vortex is not visible on the FES.  The hydrodynamic interpretation thus provides new insights into the mechanism of protein folding and can be a useful complement to std. analyses.},
	author = {Sergei F. Chekmarev and Andrey Y. Palyanov and Martin Karplus}
}
@article {113101,
	title = {How subunit coupling produces the γ-​subunit rotary motion in F1-​ATPase},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {105},
	year = {2008},
	pages = {1192-1197},
	abstract = {F0F1-​ATP synthase manufs. the energy "currency,​" ATP, of living cells.  The sol. F1 portion, called F1-​ATPase, can act as a rotary motor, with ATP binding, hydrolysis, and product release, inducing a torque on the γ-​subunit.  A coarse-​grained plastic network model is used to show at a residue level of detail how the conformational changes of the catalytic β-​subunits act on the γ-​subunit through repulsive van der Waals interactions to generate a torque that drives unidirectional rotation, as obsd. exptl.  The simulations suggest that the calcd. 850 substep rotation is driven primarily by ATP binding and that the subsequent 35{\textdegree} substep rotation is produced by product release from one β-​subunit and a concomitant binding pocket expansion of another β-​subunit.  The results of the simulation agree with previously reported single-​mol. expts. and support a tri-​site rotary mechanism for F1-​ATPase under physiol. conditions.},
	author = {Jingzhi Pu and Martin Karplus}
}
@article {110761,
	title = {A differential fluctuation theorem},
	journal = {J. Phys. Chem. B},
	volume = {112},
	year = {2008},
	pages = {6168-6174},
	abstract = {We derive a nonequil. thermodn. identity (the "differential fluctuation theorem") that connects forward and reverse joint probabilities of nonequil. work and of arbitrary generalized coordinates corresponding to states of interest.  This identity allows us to est. the free energy difference between domains of these states.  Our results follow from a general symmetry relation between avs. over nonequil. forward and backward path functions derived by Crooks (Crooks, G. E. 2000)​.  We show how several existing nonequil. thermodn. identities can be obtained directly from the differential fluctuation theorem.  We devise an approach for measuring conformational free energy differences, and we demonstrate its applicability to the anal. of mol. dynamics simulations by estg. the free energy difference between two conformers of the alanine dipeptide model system.  We anticipate that these developments can be applied to the anal. of lab. expts.},
	author = {Paul Maragakis and Martin Spichty and Martin Karplus}
}
@article {110756,
	title = {The elastic properties of the structurally characterized myosin II S2 subdomain: a molecular dynamics and normal mode analysis},
	journal = {Biophysical Journal},
	volume = {94},
	year = {2008},
	pages = {3779-3789},
	abstract = {The elastic properties (stretching and bending moduli) of myosin are expected to play an important role in its function.  Of particular interest is the extended α-​helical coiled-​coil portion of the mol.  Since there is no high resoln. structure for the entire coiled-​coil, a study is made of the scallop myosin II S2 subdomain for which an x-​ray structure is available (Protein Data Bank 1nkn)​.  The authors est. the stretching and bending moduli of the S2 subdomain with an at. level model by use of mol. simulations.  Results were obtained from nonequil. mol. dynamics simulations in the presence of an external force, from the fluctuations in equil. mol. dynamics simulations and from normal modes.  In addn., a poly-​Ala (78 amino acid residues) α-​helix model was examd. to test the methodol. and because of its interest as part of the lever arm.  As expected, both the α-​helix and coiled-​coil S2 subdomain are very stiff for stretching along the main axis, with the stretching stiffness const. in the range 60-​80 pN​/nm (scaled to the 60 nm long S2)​.  Both mols. are much more flexible for bending with a lateral stiffness of \~{}0.010pN​/nm for the S2 and 0.0055pN​/nm for the α-​helix (scaled to 60 nm)​.  These results are expected to be useful in estg. cross-​bridge elasticity, which is required for understanding the strain-​dependent transitions in the actomyosin cycle and for the development of three-​dimensional models of muscle contraction.
},
	author = {Ivana Adamovic and Mijailovich, Srboljub M. and Martin Karplus}
}
@article {110751,
	title = {One-​Dimensional Barrier-​Preserving Free-​Energy Projections of a β-​sheet Miniprotein: New Insights into the Folding Process},
	journal = {J. Phys. Chem. B},
	volume = {112},
	year = {2008},
	pages = {8701-8714},
	abstract = {The conformational space of a 20-​residue three-​stranded antiparallel β-​sheet peptide (double hairpin) was sampled by equil. folding​/unfolding mol. dynamics simulations for a total of 20 μs.  The resulting one-​dimensional free-​energy profiles (FEPs) provide a detailed description of the free-​energy basins and barriers for the folding reaction.  The similarity of the FEPs obtained using the probability of folding before unfolding (pfold) or the mean first passage time supports the robustness of the procedure.  The folded state and the most populated free-​energy basins in the denatured state are described by the one-​dimensional FEPs, which avoid the overlap of states present in the usual one- or two-​dimensional projections.  Within the denatured state, a basin with fluctuating helical conformations and a heterogeneous entropic state are populated near the melting temp. at about 11​\% and 33​\%, resp.  Folding pathways from the helical basin or enthalpic traps (with only one of the two hairpins formed) reach the native state through the entropic state, which is on-​pathway and is sepd. by a low barrier from the folded state.  A simplified equil. kinetic network based on the FEPs shows the complexity of the folding reaction and indicates, as augmented by addnl. analyses, that the basins in the denatured state are connected primarily by the native state.  The overall folding kinetics shows single-​exponential behavior because barriers between the non-​native basins and the folded state have similar heights.},
	author = {Sergei V. Krivov and Stefanie Muff and Amedeo Caflisch and Martin Karplus}
}
@article {110736,
	title = {Force generation in kinesin hinges on cover-​neck bundle formation. [Erratum to document cited in CA148:208527]},
	journal = {Structure},
	volume = {16},
	year = {2008},
	pages = {1147},
	abstract = {On page 68, in Figure 6B, the direction of the arrow for the rotation R1 was reversed.  The corresponding explanation on page 69, right column, last paragraph, line 2 should also be cor. to "A counterclockwise \~{}20{\textdegree} rotation.".  This change has no effect on the main results or conclusions of the paper.  Furthermore, while the 20{\textdegree} rotation in the AMPPNP state has been obsd. for Kif1A, another study on Unc104 in the same Kinesin-​3 family found that the head rotates by less than 5{\textdegree} (Al-​Bassam et al., [2008] J. Cell. Biol. 163, 743-​753.)​.},
	author = {Wonmuk Hwang and Matthew J. Lang and Martin Karplus}
}
@article {110726,
	title = {Bayesian estimates of free energies from nonequilibrium work data in the presence of instrument noise},
	journal = {J. Chem. Phys.},
	volume = {129},
	year = {2008},
	pages = {024102/1-024102/8},
	abstract = {The Jarzynski equality and the fluctuation theorem relate equil. free energy differences to nonequil. measurements of the work.  These relations extend to single-​mol. expts. that have probed the finite-​time thermodn. of proteins and nucleic acids.  The effects of exptl. error and instrument noise have not been considered previously.  Here, we present a Bayesian formalism for estg. free energy changes from nonequil. work measurements that compensates for instrument noise and combines data from multiple driving protocols.  We reanalyze a recent set of expts. in which a single RNA hairpin is unfolded and refolded using optical tweezers at three different rates.  Interestingly, the fastest and farthest-​from-​equil. measurements contain the least instrumental noise and, therefore, provide a more accurate est. of the free energies than a few slow, more noisy, near-​equil. measurements.  The methods we propose here will extend the scope of single-​mol. expts.; they can be used in the anal. of data from measurements with at. force microscopy, optical, and magnetic tweezers. },
	author = {Paul Maragakis and Felix Ritort and Carlos Bustamante and Martin Karplus and Gavin E. Crooks}
}
@article {110716,
	title = {The Human Cytomegalovirus UL44 C Clamp Wraps around DNA},
	journal = {Structure},
	volume = {16},
	year = {2008},
	pages = {1214-1225},
	abstract = {Processivity factors tether the catalytic subunits of DNA polymerases to DNA so that continuous synthesis of long DNA strands is possible.  The human cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-​shaped dimer intermediate in structure between monomeric herpes simplex virus UL42, which binds DNA directly via a basic surface, and the trimeric sliding clamp PCNA, which encircles DNA.  To investigate how UL44 interacts with DNA, calcns. were performed in which a 12 bp DNA oligonucleotide was docked to UL44.  The calcns. suggested that UL44 encircles DNA, which interacts with basic residues both within the cavity of the C clamp and in flexible loops of UL44 that complete the "circle.".  The results of mutational and crosslinking studies were consistent with this model.  Thus, UL44 is a "hybrid" of UL42 and PCNA: its structure is intermediate between the two and its mode of interaction with DNA has elements of both.},
	author = {Gloria Komazin-Meredith and Robert J. Petrella and Webster L. Santos and David J. Filman and James M. Hogle and Verdine, Gregory L. and Martin Karplus and Donald M. Coen}
}
@article {110706,
	title = {Allostery and cooperativity revisited},
	journal = {Protein Science},
	volume = {17},
	year = {2008},
	pages = {1295-1307},
	abstract = {A review.  Although phenomenol. models that account for cooperativity in allosteric systems date back to the early and mid-​60{\textquoteright}s [e.g., the D. E. Koshland, G. Nemethy, and D. Filmer, 1966 (KNF) and J. Momod, J. Wyman, and J. P. Changeux, 1965 (MWC) models]​, there is resurgent interest in the topic due to the recent exptl. and computational studies that attempted to reveal, at an atomistic level, how allostery actually works.  Here, using systems for which atomistic simulations have been carried out in their groups as examples, the authors describe the current understanding of allostery and how the mechanisms go beyond the classical MWC​/Pauling-​KNF descriptions, and point out that the "new view" of allostery, emphasizing "population shifts,​" is, in fact, an "old view.".  The presentation offers not only an up-​to-​date description of allostery from a theor.​/computational perspective, but also helps to resolve several outstanding issues concerning allostery.},
	author = {Qiang Cui and Martin Karplus}
}
@article {110701,
	title = {Diffusive reaction dynamics on invariant free energy profiles},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {105},
	year = {2008},
	pages = {13841-13846},
	abstract = {A fundamental problem in the anal. of protein folding and other complex reactions in which the entropy plays an important role is the detn. of the activation free energy from exptl. measurements or computer simulations.  This article shows how to combine min.-​cut-​based free energy profiles (FC)​, obtained from equil. mol. dynamics simulations, with conventional histogram-​based free energy profiles (FH) to ext. the coordinate-​dependent diffusion coeff. on the FC (i.e., the method dets. free energies and a diffusive preexponential factor along an appropriate reaction coordinate)​.  The FC, in contrast to the FH, is shown to be invariant with respect to arbitrary transformations of the reaction coordinate, which makes possible partition of configuration space into basins in an invariant way.  A "natural coordinate,​" for which FH and FC differ by a multiplicative const. (const. diffusion coeff.)​, is introduced.  The approach is illustrated by a model one-​dimensional system, the alanine dipeptide, and the folding reaction of a double β-​hairpin miniprotein.  It is shown how the results can be used to test whether the putative reaction coordinate is a good reaction coordinate.},
	author = {Sergei V. Krivov and Martin Karplus}
}
@article {110696,
	title = {Allosteric communication in myosin V: from small conformational changes to large directed movements},
	journal = {PLoS Computational Biology},
	volume = {4},
	year = {2008},
	pages = {e1000129:1-19},
	abstract = {The rigor to post-​rigor transition in myosin, a consequence of ATP binding, plays an essential role in the Lymn-​Taylor functional cycle because it results in the dissocn. of the actomyosin complex after the powerstroke.  On the basis of the x-​ray structures of myosin V, we have developed a new normal mode superposition model for the transition path between the two states.  Rigid-​body motions of the various subdomains and specific residues at the subdomain interfaces are key elements in the transition.  The allosteric communication between the nucleotide binding site and the U50​/L50 cleft is shown to result from local changes due to ATP binding, which induce large amplitude motions that are encoded in the structure of the protein.  The triggering event is the change in the interaction of switch I and the P-​loop, which is stabilized by ATP binding.  The motion of switch I, which is a relatively rigid element of the U50 subdomain, leads directly to a partial opening of the U50​/L50 cleft; the latter is expected to weaken the binding of myosin to actin.  The calcd. transition path demonstrates the nature of the subdomain coupling and offers an explanation for the mutual exclusion of ATP and actin binding.  The mechanism of the uncoupling of the converter from the motor head, an essential part of the transition, is elucidated.  The origin of the partial untwisting of the central β-​sheet in the rigor to post-​rigor transition is described.},
	author = {Marco Cecchini and Anne M. Houdusse and Martin Karplus}
}
@article {110691,
	title = {Kinesin{\textquoteright}s cover-​neck bundle folds forward to generate force},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {105},
	year = {2008},
	pages = {19247-19252},
	abstract = {Each step of the kinesin motor involves a force-​generating mol. rearrangement.  Although significant progress has been made in elucidating the broad features of the kinesin mechanochem. cycle, mol. details of the force generation mechanism remain a mystery.  Recent mol. dynamics simulations have suggested a mechanism in which the forward drive is produced when the N-​terminal cover strand forms a β-​sheet with the neck linker to yield the cover-​neck bundle.  We tested this proposal by comparing optical trapping motility measurements of cover strand mutants with the wild-​type.  Motility data, as well as kinetic analyses, revealed impairment of the force-​generating capacity accompanied by a greater load dependence in the mechanochem. cycle.  In particular, a mutant with the cover strand deleted functioned only marginally, despite the fact that the cover strand, the N-​terminal "dangling end,​" unlike the neck linker and nucleotide-​binding pocket, is not involved with any previously considered energy transduction pathway.  Furthermore, a const. assisting load, likely in lieu of a power stroke, was shown to rescue forward motility in the cover strand deletion mutant.  Our results support a stepping mechanism driven by dynamic cover-​neck bundle formation.  They also suggest a strategy to generate motors with altered mech. characteristics by targeting the force-​generating element.},
	author = {Ahmad S. Khalil and David C. Appleyard and Anna K. Labno and Adrien Georges and Martin Karplus and Angela M. Belcher and Wonmuk Hwang and Matthew J. Lang}
}
@article {113231,
	title = {Probing Polar Solvation Dynamics in Proteins: A Molecular Dynamics Simulation Analysis},
	journal = {J. Phys. Chem. B},
	volume = {111},
	year = {2007},
	pages = {1482-1490},
	abstract = {Measurements of time-​resolved Stokes shifts on picosecond to nanosecond time scales have been used to probe the polar solvation dynamics of biol. systems.  Since it is difficult to decomp. the measurements into protein and solvent contributions, computer simulations are useful to aid in understanding the details of the mol. behavior.  Here the authors report the anal. of simulations of the electrostatic interactions of the rest of the protein and the solvent with 11 residues of the Ig binding domain B1 of protein G.  It is shown that the polar solvation dynamics are position-​dependent and highly heterogeneous.  The contributions due to interactions with the protein and with the solvent are detd.  The solvent contributions are found to vary from negligible after a few picoseconds to dominant on a scale of hundreds of picoseconds.  The origin for the latter is found to involve coupled hydration and protein conformational dynamics.  The resulting microscopic picture demonstrates that a wide range of possibilities have to be considered in the interpretation of time-​resolved Stokes shift measurements.},
	author = {Andrei A. Golosov and Martin Karplus}
}
@article {113206,
	title = {A Lattice Protein with an Amyloidogenic Latent State: Stability and Folding Kinetics},
	journal = {J. Phys. Chem. B},
	volume = {111},
	year = {2007},
	pages = {2675-2687},
	abstract = {We have designed a model lattice protein that has two stable folded states, the lower free energy native state and a latent state of somewhat higher energy.  The two states have a sizable part of their structures in common (two "α-​helixes") and differ in the content of "α-​helixes" and "β-​strands" in the rest of their structures; i.e.  For the native state, this part is α-​helical, and for the latent state it is composed of β-​strands.  Thus, the lattice protein free energy surface mimics that of amyloidogenic proteins that form well organized fibrils under appropriate conditions.  A Go-​like potential was used and the folding process was simulated with a Monte Carlo method.  To gain insight into the equil. free energy surface and the folding kinetics, we have combined std. approaches (reduced free energy surfaces, contact maps, time-​dependent populations of the characteristic states, and folding time distributions) with a new approach.  The latter is based on a principal coordinate anal. of the entire set of contacts, which makes possible the introduction of unbiased reaction coordinates and the construction of a kinetic network for the folding process.  The system is found to have four characteristic basins, namely a semicompact globule, an on-​pathway intermediate (the bifurcation basin)​, and the native and latent states.  The bifurcation basin is shallow and consists of the structure common to the native and latent states, with the rest disorganized.  On the basis of the simulation results, a simple kinetic model describing the transitions between the characteristic states was developed, and the rate consts. for the essential transitions were estd.  During the folding process the system dwells in the bifurcation basin for a relatively short time before it proceeds to the native or latent state.  We suggest that such a bifurcation may occur generally for proteins in which native and latent states have a sizable part of their structures in common.  Moreover, there is the possibility of introducing changes in the system (e.g., mutations)​, which guide the system toward the native or misfolded state.},
	author = {Andrey Y. Palyanov and Sergei V. Krivov and Martin Karplus and Sergei F. Chekmarev}
}
@article {113181,
	title = {A Kinetic Model of Coordinated Myosin V},
	journal = {Biochemistry},
	volume = {46},
	year = {2007},
	pages = {6318-6330},
	abstract = {We present a kinetic model for the walking of myosin V on actin under conditions of zero external force.  The model includes three pathways and the termination of the processivity.  Exptl. measured kinetic parameters are used in the model to obtain quant. results.  Using the model and assocd. parameters, we compute the proportion of the pathway contg. an intermediate state, as well as the walking velocities and run lengths at various concns. of ATP and ADP.  The resulting trends agree with exptl. data.  The model explains the surprising exptl. finding that myosin walks at a faster speed but for a shorter distance as the ATP concn. increases in the absence of ADP.  It also suggests that under physiol. condition ([ADP] \~{} 12-​50 μM)​, myosin walks with a higher speed and for longer distances when ATP is more abundant.},
	author = {Yudong Wu and Yi Qin Gao and Martin Karplus}
}
@article {113166,
	title = {Minimum free energy pathways and free energy profiles for conformational transitions based on atomistic molecular dynamics simulations},
	journal = {J. Chem. Phys.},
	volume = {126},
	year = {2007},
	pages = {164106/1-164106/17},
	abstract = {An efficient method for the calcn. of min. free energy pathways and free energy profiles for conformational transitions is presented.  Short restricted perturbation-​targeted mol. dynamics trajectories are used to generate an approx. free energy surface.  Approx. reaction pathways for the conformational change are constructed from one-​dimensional line segments on this surface using a Monte Carlo optimization.  Accurate free energy profiles are then detd. along the pathways by means of one-​dimensional adaptive umbrella sampling simulations.  The method is illustrated by its application to the alanine "dipeptide.".  Due to the low computational cost and memory demands, the method is expected to be useful for the treatment of large biomol. systems.},
	author = {Arjan van der Vaart and Martin Karplus}
}
@article {113151,
	title = {The Signaling Pathway of Rhodopsin},
	journal = {Structure},
	volume = {15},
	year = {2007},
	pages = {611-623},
	abstract = {The signal-​transduction mechanism of rhodopsin was studied by mol. dynamics (MD) simulations of the high-​resoln., inactive structure in an explicit membrane environment.  The simulations were employed to calc. equal-​time correlations of the fluctuating interaction energy of residue pairs.  The resulting interaction-​correlation matrix was used to det. a network that couples retinal to the cytoplasmic interface, where transducin binds.  Two highly conserved motifs, D(E)​RY and NPxxY, were found to have strong interaction correlation with retinal.  MD simulations with restraints on each transmembrane helix indicated that the major signal-​transduction pathway involves the interdigitating side chains of helixes VI and VII.  The functional roles of specific residues were elucidated by the calcd. effect of retinal isomerization from 11-​cis to all-​trans on the residue-​residue interaction pattern.  It is suggested that Glu134 may act as a "signal amplifier" and that Asp83 may introduce a threshold to prevent background noise from activating rhodopsin.},
	author = {Yifei Kong and Martin Karplus}
}
@article {113146,
	title = {Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-​DR4},
	journal = {Journal of Computer-Aided Molecular Design},
	volume = {21},
	year = {2007},
	pages = {395-418},
	abstract = {Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compds.  Although these "random" methods sample larger areas of chem. space than traditional synthetic approaches, only a relatively small percentage of all possible compds. are practically accessible.  It is therefore helpful to select regions of chem. space that have greater likelihood of yielding useful leads.  When three-​dimensional structural data are available for the target mol. this can be achieved by applying structure-​based computational design methods to focus the combinatorial library.  This is advantageous over the std. usage of computational methods to design a small no. of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to det. a propensity for binding of certain chem. moieties in regions of the target mol.  This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-​based design tool, to design a focused combinatorial library for the class II MHC protein HLA-​DR4.  Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved.  Although the structure of the protein-​ligand complex could not be detd., exptl. results including cross-​exclusion of a known HLA-​DR4 peptide ligand (HA) by a compd. from the library.  Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.},
	author = {Erik Evensen and Diane Joseph-McCarthy and Gregory A. Weiss and Schreiber, Stuart L. and Martin Karplus}
}
@article {113131,
	title = {Importance of Metastable States in the Free Energy Landscapes of Polypeptide Chains},
	journal = {Phys. Rev. Lett.},
	volume = {99},
	year = {2007},
	pages = {178104/1-178104/4},
	abstract = {We show that the interplay between excluded vol. effects, hydrophobicity, and hydrogen bonding in a tubelike representation of a polypeptide chain gives rise to free energy landscapes that in addn. to a clear global min., are characterized by the general presence of a small no. of metastable min., which correspond to common structural motifs obsd. in proteins.  The complexity of the landscape increases only moderately with the length of the chain.  Anal. of the temp. dependence of these landscapes reveals that the stability of specific metastable states is maximal at a temp. close to the midpoint of folding.  These metastable states are therefore likely to be of particular significance in detg. the generic tendency of proteins to aggregate into potentially pathogenic agents.},
	author = {Stefan Auer and Mark A. Miller and Sergei V. Krivov and Christopher M. Dobson and Martin Karplus and Vendruscolo, Michele}
}
@article {113121,
	title = {A hierarchy of timescales in protein dynamics is linked to enzyme catalysis},
	journal = {Nature},
	volume = {450},
	year = {2007},
	pages = {913-916},
	abstract = {The synergy between structure and dynamics is essential to the function of biol. macromols.  Thermally driven mol. dynamics on different timescales have been exptl. obsd. or simulated, and a direct link between micro- to milli-​second domain motions and enzymic function has been established.  However, very little is understood about the connection of these functionally relevant, collective movements with local at. fluctuations, which are much faster.  Here, the authors show that pico- to nano-​second timescale at. fluctuations in hinge regions of adenylate kinase (AK) facilitate the large-​scale, slower lid motions that produce a catalytically competent state.  The fast, local mobilities differed between mesophilic and hyperthermophilic AKs, but were strikingly similar at temps. at which enzymic activity and free energy of folding were matched.  The connection between different timescales and the corresponding amplitudes of motions in AK and their linkage to catalytic function is likely to be a general characteristic of protein energy landscapes.},
	author = {Katherine A. Henzler-Wildman and Ming Lei and Vu Thai and S. Jordan Kerns and Martin Karplus and Dorothee Kern}
}
@article {113116,
	title = {Intrinsic motions along an enzymatic reaction trajectory},
	journal = {Nature},
	volume = {450},
	year = {2007},
	pages = {838-844},
	abstract = {The mechanisms by which enzymes achieve extraordinary rate acceleration and specificity have long been of key interest in biochem.  It is generally recognized that substrate binding coupled to conformational changes of the substrate-​enzyme complex aligns the reactive groups in an optimal environment for efficient chem.  Although chem. mechanisms have been elucidated for many enzymes, the question of how enzymes achieve the catalytically competent state has only recently become approachable by expt. and computation.  Here, the authors show crystallog. evidence for conformational substates along the trajectory toward the catalytically competent {\textquoteright}closed{\textquoteright} state in the ligand-​free form of adenylate kinase.  Mol. dynamics simulations indicate that these partially closed conformations are sampled in nanoseconds, whereas NMR and single-​mol. fluorescence resonance energy transfer reveal rare sampling of a fully closed conformation occurring on the microsecond-​to-​millisecond timescale.  Thus, the larger-​scale motions in substrate-​free adenylate kinase are not random, but preferentially follow the pathways that create the configuration capable of proficient chem.  Such preferred directionality, encoded in the fold, may contribute to catalysis in many enzymes.},
	author = {Katherine A. Henzler-Wildman and Vu Thai and Ming Lei and Maria Ott and Magnus Wolf-Watz and Tim Fenn and Ed Pozharski and Mark A. Wilson and Gregory A. Petsko and Martin Karplus}
}
@article {113996,
	title = {The Allosteric Mechanism of Yeast Chorismate Mutase: A Dynamic Analysis},
	journal = {Journal of Molecular Biology},
	volume = {356},
	year = {2006},
	pages = {237-247},
	abstract = {The effector-​regulated allosteric mechanism of yeast chorismate mutase (YCM) was studied by normal mode anal. and targeted mol. dynamics.  The normal mode anal. shows that the conformational change between YCM in the R state and in the T state can be represented by a relatively small no. of low-​frequency modes.  This suggests that the transition is coded in the structure and is likely to have a low energetic barrier.  Quant. comparisons (i.e. frequencies) between the low-​frequency modes of YCM with and without effectors (modeled structures) reveal that the binding of Trp increases the global flexibility, whereas Tyr decreases global flexibility.  The targeted mol. dynamics simulation of substrate analog release from the YCM active site suggests that a series of residues are crit. for orienting and "recruiting" the substrate.  The simulation led to the switching of a series of substrate-​release-​coupled salt-​bridge partners in the ligand-​binding domain; similar changes occur in the transition between YCM R-​state and T-​state crystal structures.  Thus, the normal mode anal. and targeted mol. dynamics results provide evidence that the effectors regulate YCM activity by influencing the global flexibility.  The change in flexibility is coupled to the binding of substrate to the T state and release of the product from the R state, resp.},
	author = {Yifei Kong and Jianpeng Ma and Martin Karplus and William N. Lipscomb}
}
@article {113991,
	title = {Two-​Metal-​Ion Mechanism for Hammerhead-​Ribozyme Catalysis},
	journal = {J. Phys. Chem. B},
	volume = {110},
	year = {2006},
	pages = {3395-3409},
	abstract = {The hammerhead ribozyme is one of the best studied ribozymes, but it still presents challenges for our understanding of RNA catalysis.  It catalyzes a transesterification reaction that converts a 5{\textquoteright},​3{\textquoteright} diester to a 2{\textquoteright},​3{\textquoteright} cyclic phosphate diester via an SN2 mechanism.  Thus, the overall reaction corresponds to that catalyzed by bovine pancreatic RNase.  However, an essential distinguishing aspect is that metal ions are not involved in RNase catalysis but appear to be important in ribozymes.  Although various techniques have been used to assign specific functions to metals in the hammerhead ribozyme, their no. and roles in catalysis is not clear.  Two recent theor. studies on RNA catalysis examd. the reaction mechanism of a single-​metal-​ion model.  A two-​metal-​ion model, which is supported by expt. and based on ab initio and d. functional theory calcns., is described here.  The proposed mechanism of the reaction has four chem. steps with three intermediates and four transition states along the reaction pathway.  Reaction profiles are calcd. in the gas phase and in soln.  The early steps of the reaction are found to be fast (with low activation barriers)​, and the last step, corresponding to the departure of the leaving group, is rate limiting.  This two-​metal-​ion model differs from the models proposed previously in that the two metal ions function not only as Lewis acids but also as general acids​/bases.  Comparison with expt. shows good agreement with thermodn. and kinetic data.  A detailed anal. based on natural bond orbitals (NBOs) and natural energy decompn. (NEDA) provides insights into the role of metal ions and other factors important for catalysis.},
	author = {Fabrice Leclerc and Martin Karplus}
}
@article {113966,
	title = {Optimal Estimates of Free Energies from Multistate Nonequilibrium Work Data},
	journal = {Phys. Rev. Lett.},
	volume = {96},
	year = {2006},
	pages = {100602/1-100602/4},
	abstract = {We derive the optimal ests. of the free energies of an arbitrary no. of thermodn. states from nonequil. work measurements; the work data are collected from forward and reverse switching processes and obey a fluctuation theorem.  The max. likelihood formulation properly reweights all pathways contributing to a free energy difference and is directly applicable to simulations and expts.  We demonstrate dramatic gains in efficiency by combining the anal. with parallel tempering simulations for alchem. mutations of model amino acids.},
	author = {Paul Maragakis and Martin Spichty and Martin Karplus}
}
@article {113941,
	title = {Folding of Ubiquitin: A Simple Model Describes the Strange Kinetics},
	journal = {J. Phys. Chem. B},
	volume = {110},
	year = {2006},
	pages = {8865-8869},
	abstract = {The ubiquitin mutant Ub*G folding expts. of Sabelko et al. (Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 6031-​6036)​, in which "strange kinetics" were obsd., are interpreted in terms of a simple kinetic model.  A minimal set of states consisting of a semicompact globule, two off-​pathway traps, and the native state are included; the fully unfolded state is not considered because folding to the semicompact globule is fast.  Both the low- and the high-​temp. expts. of Sabelko et al.  Are fitted by a system of kinetic equations detg. the transitions between these states.  It is possible that cold- and heat-​denaturated states of Ub*G are the basis of the off-​pathway traps.  The fits of the kinetic model to the exptl. results provides an est. of the rate consts. for the various reaction channels and show how their contributions vary with temp.  Introduction of an on-​pathway intermediate instead of one of the off-​pathway traps does not lead to agreement with the expts.},
	author = {Sergei F. Chekmarev and Sergei V. Krivov and Martin Karplus}
}
@article {113931,
	title = {Dynamic Distance Disorder in Proteins Is Caused by Trapping},
	journal = {J. Phys. Chem. B},
	volume = {110},
	year = {2006},
	pages = {9363-9367},
	abstract = {Dynamic disorder in proteins, as demonstrated by variations in single-​mol. electron transfer rates, is investigated by mol. dynamics simulations.  The potential of mean force for the fluctuating donor-​acceptor distance is calcd. for the NAD(P)​H:flavin oxidoreductase (Fre) complex with FAD and is found to be in agreement with that estd. from electron transfer expts.  The calcd. autocorrelation function of the distance fluctuations has a simple exponential behavior at low temps. and stretched exponential behavior at higher temps. on femtosecond to nanosecond time scales.  This indicates that the calcd. dynamic disorder arises from a wide range of trapping times in potential wells on the protein energy landscape and suggests a corresponding origin for the stretched exponential behavior obsd. exptl. on longer time scales.},
	author = {Guobin Luo and Ioan Andricioaei and X. Sunney Xie and Martin Karplus}
}
@article {113926,
	title = {Conformational sampling via a self-​regulating effective energy surface},
	journal = {J. Chem. Phys.},
	volume = {124},
	year = {2006},
	pages = {174901/1-174901/15},
	abstract = {The difficulty of efficiently sampling the phase space of complex systems with rough energy surfaces is well known.  Typical solns. to the problem involve accelerating the crossing of barriers, but such methods often have the secondary problem that the low-​energy states of interest are inadequately sampled, unless the parameters of the search algorithm are modified as the system evolves.  A method is presented to improve the sampling with particular emphasis on the low-​energy conformations, which make the most important contributions to the thermodn. of the system.  The algorithm proposed here samples the details of the min., while easily surmounting barriers.  This is achieved by introducing a self-​regulating sampling variable which depends on the current state of the system.  Two replicas of the system are introduced and the sampling variable is treated as a particle coupled to the phys. system.  The method is illustrated with a simple model system and is applied to the realistic example of barrier crossing in a protein-​ligand complex.},
	author = {Ryan Bitetti-Putzer and Aaron R. Dinner and Wei Yang and Martin Karplus}
}
@article {113921,
	title = {Nucleophilic Attack on Phosphate Diesters: A Density Functional Study of In-​Line Reactivity in Dianionic, Monoanionic, and Neutral Systems},
	journal = {J. Phys. Chem. B},
	volume = {110},
	year = {2006},
	pages = {11525-11539},
	abstract = {A d. functional study of the hydrolysis reaction of phosphodiesters with a series of attacking nucleophiles in the gas phase and in soln. is presented.  The nucleophiles HOH, HO-​, CH3OH, and CH3O-​ were studied in reactions with ethylene phosphate, 2{\textquoteright},​3{\textquoteright}-​ribose cyclic phosphate and in their neutral (protonated) and monoanionic forms.  Stationary-​point geometries for the reactions were detd. at the d. functional B3LYP​/6-​31++G(d,​p) level followed by energy refinement at the B3LYP​/6-​311++G(3df,​2p) level.  Solvation effects were estd. by using a dielec. approxn. with the polarizable continuum model (PCM) at the gas-​phase optimized geometries.  This series of reactions characterizes factors that influence the intrinsic reactivity of the model phosphate compds., including the effect of nucleophile, protonation state, cyclic structure, and solvent.  The present study of the in-​line mechanism for phosphodiester hydrolysis, a reaction of considerable biol. importance, has implications for enzymic mechanisms.  The anal. generally supports the associative mechanism for phosphate ester hydrolysis.  The results highlight the importance for the reaction barrier of charge neutralization resulting from the protonation of the nonbridging phosphoryl oxygens and the role of internal hydrogen transfer in the gas-​phase mechanism.  It also shows that solvent stabilization has a profound influence on the relative barrier heights for the dianionic, monoanionic, and neutral reactions.  The calcns. provide a comprehensive data set for the in-​line hydrolysis mechanisms that can be used for the development of improved semiempirical quantum models for phosphate hydrolysis reactions.},
	author = {Xabier Lopez and Annick Dejaegere and Fabrice Leclerc and Darrin M. York and Martin Karplus}
}
@article {113916,
	title = {A Src-​like inactive conformation in the Abl tyrosine kinase domain},
	journal = {PLoS Computational Biology},
	volume = {4},
	year = {2006},
	pages = {753-767},
	abstract = {The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML)​.  The recognition of an inactive conformation of Abl, in which a catalytically important Asp-​Phe-​Gly (DFG) motif is flipped by approx. 180{\textdegree} with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML.  The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-​Src.  We present a structure of the kinase domain of Abl, detd. in complex with an ATP-​peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases.  An interesting aspect of the Src-​like inactive structure, suggested by mol. dynamics simulations and addnl. crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site.  One class of mutations in BCR-​Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-​like conformation than the active or imatinib-​bound conformations.  Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.},
	author = {Nicholas M. Levinson and Olga Kuchment and Kui Shen and Matthew A. Young and Michael Koldobskiy and Martin Karplus and Philip A. Cole and John Kuriyan}
}
@inbook {113906,
	title = {Spinach on the ceiling: a theoretical chemist{\textquoteright}s return to biology},
	booktitle = {Annual Review of Biophysics and Biomolecular Structure},
	volume = {35},
	year = {2006},
	pages = {1-47},
	abstract = {An autobiog. of Martin Karplus, who was born in Vienna and came to the United States as a refugee in Oct. 1938, is presented.  This experience played an important role in his view of the world and my approach to science: It contributed to his realization that it was safe to stop working in fields that he felt he understood and to focus on different areas of research by asking questions that would teach him and others something new.  He describe the experiences that led him from chem. and physics back to his first love, biol., and outline some of the contributions he has made as part of his ongoing learning experience.},
	author = {Martin Karplus}
}
@article {113901,
	title = {One-​Dimensional Free-​Energy Profiles of Complex Systems: Progress Variables that Preserve the Barriers},
	journal = {J. Phys. Chem. B},
	volume = {110},
	year = {2006},
	pages = {12689-12698},
	abstract = {We show that the balanced min.-​cut procedure introduced in PNAS 2004, 101, 14766 can be reinterpreted as a method for solving the constrained optimization problem of finding the min. cut among the cuts with a particular value of an additive function of the nodes on either side of the cut.  Such an additive function (e.g., the partition function of the reactant region) can be used as a progress coordinate to det. a one-​dimensional profile (FEP) of the free-​energy surface of the protein-​folding reaction as well as other complex reactions.  The algorithm is based on the network (obtained from an equil. mol. dynamics simulation) that represents the calcd. reaction behavior.  The resulting FEP gives the exact values of the free energy as a function of the progress coordinate; i.e., at each value of the progress coordinate, the profile is obtained from the surface with the minimal partition function among the surfaces that divide the full free-​energy surface between two chosen end points.  In many cases, the balanced min.-​cut procedure gives results for only a limited set of points.  An approx. method based on pfold is shown to provide the profile for a more complete set of values of the progress coordinate.  Applications of the approach to model problems and to realistic systems (β-​hairpin of protein G, LJ38 cluster) are presented.},
	author = {Sergei V. Krivov and Martin Karplus}
}
@article {113891,
	title = {Implications of Alternative Substrate Binding Modes for Catalysis by Uracil-​DNA Glycosylase: An Apparent Discrepancy Resolved},
	journal = {Biochemistry},
	volume = {45},
	year = {2006},
	pages = {13687-13696},
	abstract = {A theor. study showed that the base excision repair enzyme uracil-​DNA glycosylase (UDG) exploits electrostatic interactions with backbone phosphate groups in the substrate for catalysis.  Although expts. performed to test the calcd. results confirmed the predicted importance of the -​2, -​1, and +1 phosphate groups, there was an apparent disagreement with regard to the +2 phosphate group.  The calcns. indicated that it made an important contribution, while exptl., the effect of its deletion or neutralization was small.  The +2 phosphate group interacts directly with an active site histidine (H148 in humans) in the crystal structure of UDG in complex with double-​stranded (ds) DNA.  We previously calcd. that H148 has a strong anticatalytic effect due to its protonation, and here we use alchem. free energy simulations to est. its site-​specific pKa.  We find that it is pos. charged over the entire exptl. pH range (4-​10)​, so its deprotonation cannot compensate for deletion or neutralization of the +2 phosphate group.  The free energy simulations are facilitated by an efficient charge-​scaling procedure that allows quant. correction for the implicit treatment of solvent far from the active site; improvements are made to that method to account carefully for differences in the truncation of electrostatic interactions in the contributing mol.-​mech. and continuum-​electrostatic approaches.  Addnl. simulations are used to demonstrate that the +2 phosphate group is fully solvent exposed in complexes with single-​stranded DNA substrates like those used in the expts.  In contrast, it is well-​structured and buried in the dsDNA complex used in the original simulations.  Differences in solvent shielding thus account for the apparent lack of an effect obsd. exptl. upon neutralization or deletion of this group.},
	author = {Ao Ma and Jie Hu and Martin Karplus and Aaron R. Dinner}
}
@article {113886,
	title = {Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {103},
	year = {2006},
	pages = {16965-16970},
	abstract = {Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels composed of subunits that consist of an extracellular domain that carries the ligand-​binding site and a distinct ion-​pore domain.  Signal transduction results from the allosteric coupling between the two domains: the distance from the binding site to the gate of the pore domain is 50 {\r A}.  Normal mode anal. with a Cα Gaussian network of a new structural model of the neuronal α7 nAChR showed that the lowest mode involves a global quaternary twist motion that opens the ion pore.  A mol. probe anal., in which the network is modified at each individual amino acid residue, demonstrated that the major effect is to change the frequency, but not the form, of the twist mode.  The largest effects were obsd. for the ligand-​binding site and the Cys-​loop.  Most (24​/27) of spontaneous mutations known to cause congenital myasthenia and autosomal dominant nocturnal frontal lobe epilepsy are located either at the interface between subunits or, within a given subunit, at the interface between rigid blocks.  These interfaces are modified significantly by the twist mode.  The present anal., thus, supports the quaternary twist model of the nAChR allosteric transition and provides a qual. interpretation of the effect of the mutations responsible for several receptor pathologies.},
	author = {Antoine Taly and Pierre-Jean Corringer and Thomas Grutter and Lia de Carvalho and Martin Karplus and Jean-Pierre Changeux}
}
@inbook {113211,
	title = {Fragment docking to proteins with the multi-​copy simultaneous search methodology},
	booktitle = {Methods and Principles in Medicinal Chemistry},
	volume = {34},
	year = {2006},
	pages = {125-148},
	publisher = {Wiley-VCH},
	organization = {Wiley-VCH},
	edition = {Fragment-Based Approaches in Drug Discovery},
	abstract = {A review on major aspects of the multi-​copy simultaneous search methodol. used for calcg. functionality maps.},
	author = {Collin M. Stultz and Martin Karplus}
}
@article {118291,
	title = {Folding Time Distributions as an Approach to Protein Folding Kinetics},
	journal = {J. Phys. Chem. B},
	volume = {109},
	year = {2005},
	pages = {5312-5330},
	abstract = {A 27-residue lattice heteropolymer subject to Monte Carlo dynamics on a simple cubic lattice is studied over a range of temps. ~Folding time distributions are used to obtain information concerning the details of folding kinetics. ~The results are compared with those from methods based on mean force surfaces expressed in terms of a reduced set of variables and on a disconnectivity graph for the same system. ~A detailed anal. of the folding trajectories is given, and the importance of dead-end traps in detg. the folding time is demonstrated. ~We show that the calcd. folding kinetics can be modeled by a system of kinetic equations, with the essential rate consts. detd. from the Monte Carlo simulations and the resulting folding time distributions. ~The kinetic equations make possible an anal. of the variation of the importance of different channels with temp. ~In particular, we show that the presence of intermediates may be masked in the folding time distributions, with the mean folding time being independent of the height of the barrier between the intermediates and collapsed globule state of the system. ~This and other results demonstrate that care has to be used in interpreting exptl. folding data in terms of the underlying kinetics. ~Correspondingly, simulations are shown to have to satisfy certain requirements to obtain proper sampling of the dead-end traps.},
	author = {Sergei F. Chekmarev and Sergei V. Krivov and Martin Karplus}
}
@inbook {118281,
	title = {Protein structural transitions and their functional role},
	booktitle = {Philosophical Transactions of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences},
	volume = {363(1827)},
	year = {2005},
	pages = {331-356},
	abstract = {A review. ~Living cells are a collection of mol. machines which carry out many of the functions essential for the cell{\textquoteright}s existence, differentiation, and reprodn. ~Most, although not all, of these machines are made up of proteins. ~Because of their complexity, an understanding of how they work requires a synergistic combination of exptl. and theor. studies. ~Here, the authors outline and discuss their studies of 2 such protein machines. ~One is GroEL, the mol. chaperone from Escherichia coli, which aids in protein folding, and the other is F1-ATPase, a motor protein which synthesizes and hydrolyzes ATP.},
	author = {Martin Karplus and Yi Qin Gao and Jianpeng Ma and Arjan van der Vaart and Wei Yang}
}
@article {118271,
	title = {Structure of a repair enzyme interrogating undamaged DNA elucidates recognition of damaged DNA},
	journal = {Nature},
	volume = {434},
	year = {2005},
	pages = {612-618},
	abstract = {How DNA repair proteins distinguish between the rare sites of damage and the vast expanse of normal DNA is poorly understood. ~Recognizing the mutagenic lesion 8-oxoguanine (oxoG) represents an esp. formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G). ~Here we report the use of a covalent trapping strategy to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1), in the act of interrogating normal DNA. ~The x-ray structure of the trapped complex features a target G nucleobase extruded from the DNA helix but denied insertion into the lesion recognition pocket of the enzyme. ~Free energy difference calcns. show that both attractive and repulsive interactions have an important role in the preferential binding of oxoG compared with G to the active site. ~The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site.},
	author = {Anirban Banerjee and Wei Yang and Martin Karplus and Verdine, Gregory L.}
}
@article {118266,
	title = {Simulation of conformational transitions by the restricted perturbation-targeted molecular dynamics method},
	journal = {J. Chem. Phys.},
	volume = {122},
	year = {2005},
	pages = {114903/1-114903/6},
	abstract = {A method for the simulation of conformational transitions is presented. ~The method, based on targeted mol. dynamics (TMD), limits the conformational change at each mol. dynamics step to a fixed size, that minimizes the root mean square deviation from the target. ~The method is more efficient than std. TMD and yields lower energy pathways, but, like the TMD method, requires only a single mol. dynamics simulation. ~Test calcns. and comparisons with std. TMD calcns. for the alanine dipeptide with the analytic continuum electrostatics implicit solvent model are presented.},
	author = {Arjan van der Vaart}
}
@article {118261,
	title = {Design, Synthesis, and Biological Evaluation of HSP90 Inhibitors Based on Conformational Analysis of Radicicol and Its Analogues},
	journal = {Journal of the American Chemical Society},
	volume = {127},
	year = {2005},
	pages = {6999-7004},
	abstract = {The mol. chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a no. of oncogenes. ~Among the know inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. ~A mol. dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. ~The lowest of these is the bioactive conformation obsd. in the cocrystal structure of radicicol with HSP90. ~Corresponding conformational analyses of several known analogs gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. ~Based on this observation, a no. of proposed analogs were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. ~This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlamydosporia, as a potential inhibitor of HSP90. ~Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol.},
	author = {Emilie Moulin and Vincent Zoete and Sofia Barluenga and Martin Karplus and Nicolas Winssinger}
}
@article {118256,
	title = {What Contributions to Protein Side-chain Dynamics are Probed by NMR Experiments? A Molecular Dynamics Simulation Analysis},
	journal = {Journal of Molecular Biology},
	volume = {349},
	year = {2005},
	pages = {185-203},
	abstract = {Mol. dynamics simulations of the structurally homologous proteins TNfn3 and FNfn10 have been used to investigate the contributions to side-chain dynamics measured by NMR relaxation expts. ~The results reproduce the variation in core side-chain dynamics obsd. by NMR and highlight the relevance of anharmonic motion and transitions between local min. for explaining NMR side-chain order parameters. ~A method is described for calcg. converged order parameters by use of replica exchange mol. dynamics in conjunction with an implicit solvent model. ~These simulations allow the influence of various factors, such as the flexibility of side-chains and their free vol., on the mobility to be tested by perturbing the system. ~Deletion mutations are found to have the largest effect on the more densely packed FNfn10. ~Some counterintuitive effects are seen, such as an increase in order parameters close to deletion mutation sites, but these can be rationalized in terms of direct interactions with the modified side-chains. ~A statistical anal. of published order parameters supports the conclusions drawn from the simulations.},
	author = {Robert B. Best and Jane Clarke and Martin Karplus}
}
@article {118251,
	title = {Electrostatic energies and forces computed without explicit interparticle interactions: A linear time complexity formulation},
	journal = {Journal of Computational Chemistry},
	volume = {26},
	year = {2005},
	pages = {755-787},
	abstract = {A rapid method for the calcn. of the electrostatic energy of a system without a cutoff is described in which the computational time grows linearly with the no. of particles or charges. ~The inverse of the distance is approximated as a polynomial, which is then transformed into a function whose terms involve individual particles, instead of particle pairs, by a partitioning of the double sum. ~In this way, the electrostatic energy that is detd. by the interparticle interactions is obtained without explicit calcn. of these interactions. ~For systems of pos. charges positioned on a face-centered cubic lattice, the calcn. of the energy by the new method is shown to be faster than the calcn. of the exact energy, in many cases by an order of magnitude, and to be accurate to within 1-2\%. ~The application of this method to increase the accuracy of conventional truncation-based calcns. in condensed-phase systems is also demonstrated by combining the approximated long-range electrostatic interactions with the exact short-range interactions in a "hybrid" calcn. ~For a 20-{\r A} sphere of water mols., the forces are shown to be six times as accurate using this hybrid method as those calcd. with conventional truncation of the electrostatic energy function at 12 {\r A}. ~This is accomplished with a slight increase in speed, and with a sevenfold increase in speed relative to the exact all-pair calcn. ~Structures minimized with the hybrid function are shown to be closer to structures minimized with an exact all-pair electrostatic energy function than are those minimized with a conventional 13-{\r A} cutoff-based electrostatic energy function. ~Comparison of the energies and forces calcd. with the exact method illustrate that the abs. errors obtained with std. truncation can be very large. ~The extension of the current method to other pairwise functions as well as to multibody functions, is described.},
	author = {Robert J. Petrella and Martin Karplus}
}
@article {118246,
	title = {Normal Mode Calculations of Icosahedral Viruses with Full Dihedral Flexibility by Use of Molecular Symmetry},
	journal = {Journal of Molecular Biology},
	volume = {350},
	year = {2005},
	pages = {528-542},
	abstract = {The study of the dynamics and thermodn. of small icosahedral virus capsids is an active field of research. ~Normal mode anal. is one of the computational tools that can provide important insights into the conformational changes of the virus assocd. with cell entry or caused by changing of the physicochem. environment. ~Normal mode anal. of virus capsids has been limited due to the size of these systems, which often exceed 50,000 residues. ~Here we present the first normal mode calcn. with full dihedral flexibility of several virus capsids, including poliovirus, rhinovirus, and cowpea chlorotic mottle virus. ~The calcns. were made possible by applying group theor. methods, which greatly simplified the calcns. without any approxn. beyond the all-atom force field representations in general use for smaller protein systems. ~Since a full Cartesian basis set was too large to be handled by the available computer memory, we used a basis set that includes all internal dihedral angles of the system with the exception of the peptide bonds, which were assumed rigid. ~The fluctuations of the normal modes are shown to correlate well with crystallog. temp. factors. ~The motions of the first several normal modes of each symmetry type are described. ~A hinge bending motion in poliovirus was found that may be involved in the mechanism by which bound small mols. inhibit conformational changes of the capsid. ~Fully flexible normal mode calcns. of virus capsids are expected to increase our understanding of virus dynamics and thermodn., and can be useful in the refinement of cryo-electron microscopy structures of viruses.},
	author = {Herman W. T. van Vlijmen and Martin Karplus}
}
@inbook {118241,
	title = {Molecular dynamics simulations of yeast chorismate mutase: substrate conformational transitions and enzymatic catalysis},
	booktitle = {Structure, Dynamics and Function of Biological Macromolecules and Assemblies},
	volume = {364},
	year = {2005},
	pages = {63-74},
	publisher = {IOS Press},
	organization = {IOS Press},
	abstract = {Mol. dynamics simulations of the allosteric enzyme chorismate mutase in yeasts are presented. ~QM/MM mol. dynamics simulations confirm the instability of the CHAIR conformation relative to that of other isomers in the gas phase, and confirm its relative instability in soln. ~Two nonreactive conformers which are more stable in soln. than CHAIR undergo rapid transformation to the (active) CHAIR conformation by interactions with the enzyme active site. ~The QM/MM potential generates transient substrate structures that are closer to the transition state than is the CHAIR conformer.},
	author = {Hong Guo and William N. Lipscomb and Qiang Cui and Martin Karplus}
}
@article {115616,
	title = {Role of Conformational Heterogeneity in Domain Swapping and Adapter Function of the Cks Proteins},
	journal = {Journal of Biological Chemistry},
	volume = {280},
	year = {2005},
	pages = {30448-30459},
	abstract = {Cks proteins are adapter mols. that coordinate the assembly of multiprotein complexes. ~They share the ability to domain swap by exchanging a β-strand, β4. ~Here we use NMR spectroscopy and mol. dynamics simulations to investigate the dynamic properties of human Cks1 and its response on assembly with components of the SCFSkp2 ubiquitin ligation machinery. ~In the NMR expt. with the free form of Cks1, a subset of residues displayed elevated R2 values and the cross-peaks of neighboring residues were missing from the spectrum, indicating a substantial conformational exchange contribution on the microsecond to millisecond time scale. ~Strikingly the region of greatest conformational variability was the β4-strand that domain swaps to form the dimer. ~Binding of the ligand common to all Cks proteins, Cdk2, suppressed the conformational heterogeneity. ~This response was specific to Cdk2 binding; in contrast, binding of Skp2, a ligand unique to human Cks1, did not alter the dynamic behavior. ~Short time (<5 ns) mol. dynamics simulations indicate that residues of Cks1 that form the binding site for phosphorylated ligands are considerably more flexible in the free form of Cks1 than they are in the Cdk2-Cks1 complex. ~A cooperative interaction between Cdk2 and Cks1 is suggested, which reduces the configurational entropy of Cks1 and therefore facilitates phosphoprotein binding. ~Indications of an unusual dynamic behavior of strand β4 in the free form of Cks1 were obtained from longer time scale (50 ns) dynamics simulations. ~A spontaneous reversible unzipping of hydrogen bonds between β4 and β2 was obsd., suggesting an early intermediate structure for unfolding and/or domain swapping. ~We propose that the dynamic properties of the β-sheet and its modification upon ligand binding underlie the domain swapping ability and the adapter function of Cks proteins.},
	author = {Markus A. Seeliger and Martin Spichty and Sadie E. Kelly and Mark Bycroft and Stefan M. V. Freund and Martin Karplus and Laura S. Itzhaki}
}
@article {115606,
	title = {Transition State Contact Orders Correlate with Protein Folding Rates},
	journal = {Journal of Molecular Biology},
	volume = {352},
	year = {2005},
	pages = {495-500},
	abstract = {We have used mol. dynamics simulations restrained by exptl. ϕ values derived from protein engineering expts. to det. the structures of the transition state ensembles of ten proteins that fold with two-state kinetics. ~For each of these proteins we then calcd. the av. contact order in the transition state ensemble and compared it with the corresponding exptl. folding rate. ~The resulting correlation coeff. is similar to that computed for the contact orders of the native structures, supporting the use of native state contact orders for predicting folding rates. ~The native contacts in the transition state also correlate with those of the native state but are found to be about 30\% lower. ~These results show that, despite the high levels of heterogeneity in the transition state ensemble, the large majority of contributing structures have native-like topologies and that the native state contact order captures this phenomenon.},
	author = {Emanuele Paci and Kresten Lindorff-Larsen and Christopher M. Dobson and Martin Karplus and Vendruscolo, Michele}
}
@article {115581,
	title = {Study of the insulin dimerization: Binding free energy calculations and per-residue free-energy decomposition},
	journal = {Proteins: Structure, Function, and Bioinformatics},
	volume = {61},
	year = {2005},
	pages = {79-93},
	abstract = {A calcn. of the binding free energy for the dimerization of insulin has been performed using the mol. mechanics-generalized Born surface area approach. ~The calcd. abs. binding free energy is -11.9 kcal/mol, in approx. agreement with the exptl. value of -7.2 kcal/mol. ~The results show that the dimerization is mainly due to nonpolar interactions. ~The role of the hydrogen bonds between the 2 monomers appears to give the direction of the interactions. ~A per-atom decompn. of the binding free energy has been performed to identify the residues contributing most to the self assocn. free energy. ~Residues B24-B26 are found to make the largest favorable contributions to the dimerization. ~Other residues situated at the interface between the 2 monomers were found to make favorable but smaller contributions to the dimerization: Tyr B16, Val B12, and Pro B28, and to an even lesser extent, Gly B23. ~The energy decompn. on a per-residue basis is in agreement with exptl. alanine scanning data. ~The results obtained from a single trajectory (i.e., the dimer trajectory is also used for the monomer anal.) and 2 trajectories (i.e., sep. trajectories are used for the monomer and dimer) are similar.},
	author = {Vincent Zoete and Markus Meuwly and Martin Karplus}
}
@article {115571,
	title = {Large Amplitude Conformational Change in Proteins Explored with a Plastic Network Model: Adenylate Kinase},
	journal = {Journal of Molecular Biology},
	volume = {352},
	year = {2005},
	pages = {807-822},
	abstract = {The plastic network model (PNM) is used to generate a conformational change pathway for Escherichia coli adenylate kinase based on two crystal structures, namely that of an open and a closed conformer. ~In this model, the energy basins corresponding to known conformers are connected at their lowest common energies. ~The results are used to evaluate and analyze the minimal energy pathways between these basins. ~The open to closed transition anal. provides an identification of hinges that is in agreement with the existing definitions based on the available X-ray structures. ~The elastic energy distribution and the Cα pseudo-dihedral variation provide similar information on these hinges. ~The ensemble of the 45 published structures for this protein and closely related proteins is shown to always be within 3.0 {\r A} of the pathway, which corresponds to a conformational change between two end structures that differ by a Cα-atom root-mean-squared deviation of 7.1 {\r A}.},
	author = {Paul Maragakis and Martin Karplus}
}
@article {115536,
	title = {Potential Energy Surface and Molecular Dynamics of MbNO: Existence of an Unsuspected FeON Minimum},
	journal = {J. Phys. Chem. B},
	volume = {109},
	year = {2005},
	pages = {21118-21125},
	abstract = {Ligands such as CO, O2, or NO are involved in the biol. function of myoglobin. ~Here we investigate the energetics and dynamics of NO interacting with the Fe(II) heme group in native myoglobin using ab initio and mol. dynamics simulations. ~At the global min. of the ab initio potential energy surface (PES), the binding energy of 23.4 kcal/mol and the Fe-NO structure compare well with the exptl. results. ~Interestingly, the PES is found to exhibit two min.: There exists a metastable, linear Fe-O-N min. in addn. to the known, bent Fe-N-O global min. conformation. ~Moreover, the T-shaped configuration is found to be a saddle point, in contrast to the corresponding min. for NO interacting with Fe(III). ~To use the ab initio results for finite temp. mol. dynamics simulations, an anal. function was fitted to represent the Fe-NO interaction. ~The simulations show that the secondary min. is dynamically stable up to 250 K and has a lifetime of several hundred picoseconds at 300 K. ~The difference in the topol. of the heme-NO PES from that assumed previously (one deep, single Fe-NO min.) suggests that it is important to use the full PES for a quant. understanding of this system. ~Why the metastable state has not been obsd. in the many spectroscopic studies of myoglobin interacting with NO is discussed, and possible approaches to finding it are outlined.},
	author = {David R. Nutt and Martin Karplus and Markus Meuwly}
}
@inbook {114066,
	title = {Glycogen phosphorylase inhibitors: A free energy perturbation analysis of glucopyranose spirohydantoin analogues},
	booktitle = {Proteins: Structure, Function, and Bioinformatics},
	volume = {61(4)},
	year = {2005},
	pages = {984-998},
	abstract = {GP catalyzes the phosphorylation of glycogen to Glc-​1-​P.  Because of its fundamental role in the metab. of glycogen, GP has been the target for a systematic structure-​assisted design of inhibitory compds., which could be of value in the therapeutic treatment of type 2 diabetes mellitus.  The most potent catalytic-​site inhibitor of GP identified to date is spirohydantoin of glucopyranose (hydan)​.  In this work, we employ MD free energy simulations to calc. the relative binding affinities for GP of hydan and two spirohydantoin analogs, methyl-​hydan and n-​hydan, in which a hydrogen atom is replaced by a methyl- or amino group, resp.  The results are compared with the exptl. relative affinities of these ligands, estd. by kinetic measurements of the ligand inhibition consts.  The calcd. binding affinity for methyl-​hydan (relative to hydan) is 3.75{\textpm}1.4 kcal​/mol, in excellent agreement with the exptl. value (3.6{\textpm}0.2 kcal​/mol)​.  For n-​hydan, the calcd. value is 1.0{\textpm}1.1 kcal​/mol, somewhat smaller than the exptl. result (2.3{\textpm}0.1 kcal​/mol)​.  A free energy decompn. anal. shows that hydan makes optimum interactions with protein residues and specific water mols. in the catalytic site.  In the other two ligands, structural perturbations of the active site by the addnl. methyl- or amino group reduce the corresponding binding affinities.  The computed binding free energies are sensitive to the preference of a specific water mol. for two well-​defined positions in the catalytic site.  The behavior of this water is analyzed in detail, and the free energy profile for the translocation of the water between the two positions is evaluated.  The results provide insights into the role of water mols. in modulating ligand binding affinities.  A comparison of the interactions between a set of ligands and their surrounding groups in x-​ray structures is often used in the interpretation of binding free energy differences and in guiding the design of new ligands.  For the systems in this work, such an approach fails to est. the order of relative binding strengths, in contrast to the rigorous free energy treatment.},
	author = {Georgios Archontis and Kim A. Watson and Qian Xie and Georgia Andreou and Evangelia D. Chrysina and Spyros E. Zographos and Nikos G. Oikonomakos and Martin Karplus}
}
@article {28766,
	title = {A Structure-Based Model for the Synthesis and Hydrolysis of ATP by F1 ATPase},
	journal = {Cell },
	volume = {123},
	year = {2005},
	pages = {195-205 },
	author = {Y. Q. Gao and W. Yang and M. Karplus}
}
@article {28761,
	title = {Molecular Dynamics and Protein Function},
	journal = {Proc. Natl. Acad. Sci. USA },
	volume = {102},
	year = {2005},
	pages = {6679-6685},
	author = {M. Karplus and J. Kuriyan}
}
@article {122901,
	title = {How enzymes work: Analysis by modern rate theory and computer simulations},
	journal = {Science},
	volume = {303},
	year = {2004},
	pages = {186-195},
	abstract = {A review and discussion. ~Advances in transition state theory and computer simulations are providing new insights into the sources of enzyme catalysis. ~Both the lowering of the activation free energy and changes in the generalized transmission coeff. (recrossing of the transition state, tunneling, and nonequil. contributions) can play a role. ~A framework for understanding these effects is presented, and the contributions of the different factors, as illustrated by specific enzymes, are identified and quantified by computer simulations. ~The resulting understanding of enzyme catalysis is used to comment on alternative proposals of how enzymes work.},
	author = {Garcia-Viloca, Mireia and Jiali Gao and Martin Karplus and Donald G. Truhlar}
}
@article {122876,
	title = {Free energy simulations: Use of reverse cumulative averaging to determine the equilibrated region and the time required for convergence},
	journal = {J. Chem. Phys.},
	volume = {120},
	year = {2004},
	pages = {2618-2628},
	abstract = {A method is proposed for improving the accuracy and efficiency of free energy simulations. ~The essential idea is that the convergence of the relevant measure (e.g., the free energy deriv. in thermodn. integration) is monitored in the reverse direction starting from the last frame of the trajectory, instead of the usual approach, which begins with the first frame and goes in the forward direction. ~This simple change in the use of the simulation data makes it straightforward to eliminate the contamination of the avs. by contributions from the equilibrating region. ~A statistical criterion is introduced for distinguishing the equilibrated (prodn.) region from the equilibrating region. ~The proposed method, called reverse cumulative averaging, is illustrated by its application to the well-studied case of the alchem. free energy simulation of ethane to methanol.},
	author = {Ryan Bitetti-Putzer and Martin Karplus and Wei Yang}
}
@article {119241,
	title = {Comparison of the transition state ensembles for folding of Im7 and Im9 determined using all-atom molecular dynamics simulations with ϕ value restraints},
	journal = {Proteins: Structure, Function, and Bioinformatics},
	volume = {54},
	year = {2004},
	pages = {513-525},
	abstract = {Delineation of the structural properties of transition states is key to deriving models for protein folding. ~Here we describe the structures of the transition states of the bacterial immunity proteins Im7 and Im9 obtained by all-atom mol. dynamics simulations with ϕ value restraints derived from protein engineering expts. ~This pair of proteins is of special interest because, at pH 7 and 10{\textdegree}, Im7 folds via an intermediate while Im9 folds with a two-state transition. ~The structures of the transition states for Im7 and Im9, together with their radii of gyration and distances from the native state, are similar. ~The typical distance between any two members of the transition state ensemble of both proteins is large, with that of Im9 nearly twice that of Im7. ~Thus, a broad range of structures make up the transition state ensembles of these proteins. ~The ensembles satisfy the set of rather low ϕ values and yet are consistent with high βT values (> 0.85 for both proteins). ~For both Im7 and Im9 the interhelical angles are highly variable in the transition state ensembles, although the native contacts between helixes I and IV are well conserved. ~By measuring the distribution of the accessible surface area for each residue we show that the hydrophobic residues that are buried in the native state remain buried in the transition state, corresponding to a hydrophobic collapse to a relatively ordered globule. ~The data provide new insights into the structural properties of the transition states of these proteins at an at. level of detail and show that mol. dynamics simulations with ϕ value restraints can significantly enhance the knowledge of the transition state ensembles (TSE) provided by the exptl. ϕ values alone.},
	author = {Emanuele Paci and Claire T. Friel and Kresten Lindorff-Larsen and Sheena E. Radford and Martin Karplus and Vendruscolo, Michele}
}
@article {119236,
	title = {The role of carbon-donor hydrogen bonds in stabilizing tryptophan conformations},
	journal = {Proteins: Structure, Function, and Bioinformatics},
	volume = {54},
	year = {2004},
	pages = {716-726},
	abstract = {Although most side-chain torsion angles correspond to low-energy rotameric positions, deviations occur with significant frequency. ~One striking example arises in Trp residues, which have an important role in stabilizing protein structures because of their size and mixed hydrophobic/hydrophilic character. ~Ten percent of Trp side-chains have unexplained conformations with χ2 near 0{\textdegree} instead of the expected 90{\textdegree}. ~The current work is a structural and energetic anal. of these conformations. ~It is shown that many Trp residues with these orientations are stabilized by three-center carbon-donor hydrogen bonds of the form C-H=X=H-C, where X is a polar hydrogen-bond acceptor in the environment of the side-chain. ~The bridging hydrogen bonds occur both within the Trp side-chain and between the side-chain and the local protein back-bone. ~Free energy maps of an isolated Trp residue in an explicit water environment show a min. corresponding to the off-rotamer peak obsd. in the crystallog. data. ~Bridging carbon-donor hydrogen bonds are also shown to stabilize onrotamer Trp conformations, and similar bridging hydrogen bonds also stabilize some off-rotamer Asp conformations. ~The present results suggest a previously unrecognized role for three-center carbon-donor hydrogen bonds in protein structures and support the view that the off-rotamer Trp side-chain orientations are real rather than artifacts of crystallog. refinements. ~Certain of the off-rotamer Trp conformations appear to have a functional role.},
	author = {Robert J. Petrella and Martin Karplus}
}
@article {119201,
	title = {Increasing Normal Modes Analysis Accuracy: The SPASIBA Spectroscopic Force Field Introduced into the CHARMM Program},
	journal = {J. Phys. Chem. A},
	volume = {108},
	year = {2004},
	pages = {4019-4029},
	abstract = {The SPASIBA spectroscopic force field has been introduced into the CHARMM program. ~The SPASIBA force field combines the van der Waals and electrostatic interactions as originally found into CHARMM with Urey-Bradley-Shimanouchi terms for bond stretching, valence angle bending, torsional and improper torsional internal coordinates. ~SPASIBA has a vibrational spectroscopic origin, and it has largely proven its efficiency in reproducing exptl. data such as vibrational wavenumbers, dipole moments, rotational barriers, conformational energy differences, and moments of inertia. ~The SPASIBA parameters have been included into CHARMM by way of a particular library which directly activates calcns. of the specific energetic terms.},
	author = {Philippe Lagant and Dmitry E. Nolde and Roland H. Stote and G{\'e}rard Vergoten and Martin Karplus}
}
@article {119136,
	title = {Theoretical investigations on Azotobacter vinelandii ferredoxin I: effects of electron transfer on protein dynamics},
	journal = {Biophysical Journal},
	volume = {86},
	year = {2004},
	pages = {1987-2007},
	abstract = {Structural, energetic, and dynamical studies of Azotobacter vinelandii ferredoxin I are presented for native and mutant forms. ~The protein contains two iron-sulfur clusters, one of which ([3Fe-4S]) is believed to play a central role in the electron-coupled proton transfer. ~Different charge sets for the [3Fe-4S] cluster in its reduced and oxidized state are calcd. with broken symmetry ab initio d. functional theory methods and used in mol. dynamics (MD) simulations. ~The validity of the ab initio calcns. is assessed by comparing partially optimized structures of the [3Fe-4S] clusters with x-ray structures. ~Possible proton transfer pathways between the protein and the iron-sulfur cluster are examd. by both MD simulations and ab initio calcns. ~The MD simulations identify three main-chain hydrogen atoms-HN(13), HN(14), and HN(16)-that are within H-bonding distance of the [3Fe-4S] cluster throughout the MD simulations. ~They could thus play a role in the proton transfer from the protein to the iron-sulfur cluster. ~By contrast, the HD2(15) atom of the Asp-15 is seldom close enough to the [3Fe-4S] cluster to transfer a proton. ~Poisson-Boltzmann calcns. indicate that there is a low, but nonzero probability, that Asp-15 is protonated at pH 7; this is a requirement for it to serve as a proton donor. ~Ab initio calcns. with a fragment model for the protein find similar behavior for the transfer of a proton from the OH of the protonated side chain and the main-chain NH of Asp-15. ~The existence of a stable salt bridge between Asp-15 and Lys-84 in the D15E mutant, vs. its absence in the wild-type, has been suggested as the cause of the difference in the rate of proton transfer. ~Extensive MD simulations were done to test this idea; the results do not support the proposal. ~The present findings, together with the available data, serve as the basis for an alternative proposal for the mechanism of the coupled electron-proton transfer reaction in ferredoxin I.},
	author = {Markus Meuwly and Martin Karplus}
}
@inbook {119126,
	title = {Biomolecular motors: the F1-ATPase paradigm},
	booktitle = {Current Opinion in Structural Biology},
	volume = {14(2)},
	year = {2004},
	pages = {250-259},
	abstract = {A review and discussion. ~The realization that many essential functions of living cells are performed by nanoscale motors consisting of protein complexes has given rise to an intense effort to understand their mechanisms. ~Considerable progress has been made in the past 2 yr by a combination of biophys. techniques and theor. anal. ~Single-mol. studies have played a spectacular role for a variety of motors including kinesin, myosin, and polymerases. ~The understanding of F1-ATPase, the smallest biomol. rotary motor, has made particular progress by the interplay of exptl. and theor. studies; the latter have provided information not available from expt.},
	author = {Martin Karplus and Yi Qin Gao}
}
@article {119121,
	title = {Chaperoned alchemical free energy simulations: A general method for QM, MM, and QM/MM potentials},
	journal = {J. Chem. Phys.},
	volume = {120},
	year = {2004},
	pages = {9450-9453},
	abstract = {A general method for alchem. free energy simulations using QM, MM, and QM/MM potential is developed by introducing "chaperones" to restrain the structures, particularly near the end points. ~A calcn. of the free energy difference between two triazole tautomers in aq. soln. is used to illustrate the method.},
	author = {Wei Yang and Ryan Bitetti-Putzer and Martin Karplus}
}
@inbook {119076,
	title = {Investigation of glucose binding sites on insulin},
	booktitle = {Proteins: Structure, Function, and Bioinformatics},
	volume = {55(3)},
	year = {2004},
	pages = {568-581},
	abstract = {Possible insulin binding sites for D-glucose have been investigated theor. by docking and mol. dynamics (MD) simulations. ~Two different docking programs for small mols. were used; Multiple Copy Simultaneous Search (MCSS) and Solvation Energy for Exhaustive Docking (SEED) programs. ~The configurations resulting from the MCSS search were evaluated with a scoring function developed to est. the binding free energy. ~SEED calcns. were performed using various values for the dielec. const. of the solute. ~It is found that scores emphasizing non-polar interactions gave a preferential binding site in agreement with that inferred from recent fluorescence and NMR NOESY expts. ~The calcd. binding affinity of -1.4 to -3.5 kcal/mol is within the measured range of -2.0{\textpm}0.5 kcal/mol. ~The validity of the binding site is suggested by the dynamical stability of the bound glucose when examd. with MD simulations with explicit solvent. ~Alternative binding sites were found in the simulations and their relative stabilities were estd. ~The motions of the bound glucose during mol. dynamics simulations are correlated with the motions of the insulin side chains that are in contact with it and with larger scale insulin motions. ~These results raise the question of whether glucose binding to insulin could play a role in its activity. ~The results establish the complementarity of mol. dynamics simulations and normal mode analyses with the search for binding sites proposed with small mol. docking programs.},
	author = {Vincent Zoete and Markus Meuwly and Martin Karplus}
}
@inbook {119071,
	title = {X-ray structural and simulation analysis of a protein mutant: The value of a combined approach},
	booktitle = {Proteins: Structure, Function, and Bioinformatics},
	volume = {55(3)},
	year = {2004},
	pages = {733-742},
	abstract = {The effect of the mutation Arg 96 to His on the stability of bacteriophage T4 lysozyme has been previously studied by calorimetric expts., X-ray crystallog., and free energy simulation techniques. ~The exptl. and calcd. values for the difference between the free energy of denaturation of the mutant and the wild type are in reasonable agreement. ~However, the two approaches led to different explanations for the loss in stability. ~To analyze the differences, a series of refinements based on the crystallog. data were performed, a no. of aspects of the simulations were reexamd., and continuum electrostatic calcns. were done to complement the latter. ~The results of those comparisons provide a better understanding of the origin of the free energy difference in this mutant. ~Furthermore, they show the importance of the combined use of simulations and crystallog. for interpreting the effects of mutations on the energetics of the system.},
	author = {Carla Mattos and Justin D. Cohen and David F. Green and Bruce Tidor and Martin Karplus}
}
@article {119066,
	title = {The Origin of Protein Sidechain Order Parameter Distributions},
	journal = {Journal of the American Chemical Society},
	volume = {126},
	year = {2004},
	pages = {7734-7735},
	abstract = {Previous work by Wand et al. (2001) showed that the NMR order parameters characterizing the amplitude of motion of protein side chains seemed to form a multimodal distribution. ~At the time, no detailed explanation of this at the mol. level was offered, yet three classes of motion were inferred. ~We have analyzed a larger published data set and found that, although the distribution is multimodal, the evidence for three classes is weak. ~More significantly, we have been able to provide a simple phys. explanation for the distributions based on the results of mol. dynamics simulations. ~This result will aid in the interpretation of data from NMR dynamics expts,},
	author = {Robert B. Best and Jane Clarke and Martin Karplus}
}
@article {118346,
	title = {A Normal Mode Analysis of Structural Plasticity in the Biomolecular Motor F1-ATPase},
	journal = {Journal of Molecular Biology},
	volume = {340},
	year = {2004},
	pages = {345-372},
	abstract = {Normal modes have been used to explore the inherent flexibility of the α, β and γ subunits of F1-ATPase in isolation and as part of the α3β3γ complex. ~It was found that the structural plasticity of the γ and β subunits, in particular, correlates with their functions. ~The N and C-terminal helixes forming the coiled-coil domain of the γ subunit are highly flexible in the isolated subunit, but more rigid in the α3β3γ complex due to interactions with other subunits. ~The globular domain of the γ subunit is structurally relatively rigid when isolated and in the α3β3γ complex; this is important for its functional role in coupling the F0 and F1 complex of ATP synthase and in inducing the conformational changes of the β subunits in synthesis. ~Most important, the character of the lowest-frequency modes of the βE subunit is highly correlated with the large βE βTP transition. ~This holds for the C-terminal domain and the nucleotide-binding domain, which undergo significant conformational transitions in the functional cycle of F1-ATPase. ~This is most evident in the ligand-free βE subunit; the flexibility in the nucleotide-binding domain is reduced somewhat in the βTP subunit in the presence of Mg2+{\textperiodcentered}ATP. ~The low-frequency modes of the α3β3γ complex show that the motions of the globular domain of the γ subunit and of the C-terminal and nucleotide binding domains of the βE subunits are coupled, in accord with their function. ~Overall, the normal mode anal. reveals that F1-ATPase, like other macromol. assemblies, has the intrinsic structural flexibility required for its function encoded in its sequence and three-dimensional structure. ~This inherent plasticity is an essential aspect of assuring a small free energy cost for the large-scale conformational transition that occurs in mol. motors.},
	author = {Qiang Cui and Guohui Li and Jianpeng Ma and Martin Karplus}
}
@article {118341,
	title = {The crystallographic structure of the aldose reductase-IDD552 complex shows direct proton donation from tyrosine 48},
	journal = {Acta Crystallographica, Section D: Biological Crystallography},
	volume = {D60},
	year = {2004},
	pages = {1347-1354},
	abstract = {The x-ray crystal structure of human aldose reductase (ALR2) in complex with the inhibitor IDD552 was detd. using crystals obtained from two crystn. conditions with different pH values (pH 5 and 8). ~In both structures the charged carboxylic head of the inhibitor binds to the active site, making hydrogen-bond interactions with His110 and Tyr48 and electrostatic interactions with NADP+. ~There is an important difference between the two structures: the observation of a double conformation of the carboxylic acid moiety of the inhibitor at pH 8, with one water mol. interacting with the main configuration. ~This is the first time that a water mol. has been obsd. deep inside the ALR2 active site. ~Furthermore, in the configuration with the lower occupancy factor the difference electron-d. map shows a clear peak (2.5σ) for the H atom in the hydrogen bond between the inhibitor{\textquoteright}s carboxylic acid and the Tyr48 side-chain O atom. ~The position of this peak implies that this H atom is shared between both O atoms, indicating possible direct proton transfer from this residue to the inhibitor. ~This fact agrees with the model of the catalytic mechanism, in which the proton is donated by the Tyr48 hydroxyl to the substrate. ~These observations are useful both in drug design and in understanding the ALR2 mechanism.},
	author = {Federico Ruiz and Isabelle Hazemann and Andre Mitschler and Andrzejj Joachimiak and Thomas Schneider and Martin Karplus and Alberto Podjarny}
}
@article {118336,
	title = {The unfolding action of GroEL on a protein substrate},
	journal = {Biophysical Journal},
	volume = {87},
	year = {2004},
	pages = {562-573},
	abstract = {A mol. dynamics simulation of the active unfolding of denatured rhodanese by GroEL mol. chaperone (chaperonin) is presented. ~The compact denatured protein was bound initially to the cis cavity and formed stable contacts with several of the subunits. ~As the cis ring apical domains of GroEL underwent the transition from the closed to the more open (ATP-bound) state, they exerted a force on rhodanese that led to the increased unfolding of certain loops. ~The contacts between GroEL and rhodanese were analyzed and their variation during the GroEL transition was shown. ~The major contacts, which gave rise to the stretching force, were found to be similar to those obsd. in crystal structures of peptides bound to the apical domains. ~The results of the simulation showed that multidomain interactions play an essential role, in accord with expts. ~Implications of the results for mutation expts. and for the action of GroEL are discussed.},
	author = {Arjan van der Vaart and Jianpeng Ma and Martin Karplus}
}
@article {118326,
	title = {A Comparison of the Dynamic Behavior of Monomeric and Dimeric Insulin Shows Structural Rearrangements in the Active Monomer},
	journal = {Journal of Molecular Biology},
	volume = {342},
	year = {2004},
	pages = {913-929},
	abstract = {Mol. dynamics (MD) simulations (5-10 ns in length) and normal mode analyses were performed for the monomer and dimer of native porcine insulin in aq. soln.; both starting structures were obtained from an insulin hexamer. ~Several simulations were done to confirm that the results obtained are meaningful. ~The insulin dimer is very stable during the simulation and remains very close to the starting x-ray structure; the RMS fluctuations calcd. from the MD simulation agree with the exptl. B-factors. ~Correlated motions were found within each of the two monomers; they can be explained by persistent non-bonded interactions and disulfide bridges. ~The correlated motions between residues B24 and B26 of the two monomers are due to non-bonded interactions between the side-chains and backbone atoms. ~For the isolated monomer in soln., the A chain and the helix of the B chain are found to be stable during 5 ns and 10 ns MD simulations. ~However, the N-terminal and the C-terminal parts of the B chain are very flexible. ~The C-terminal part of the B chain moves away from the x-ray conformation after 0.5-2.5 ns and exposes the N-terminal residues of the A chain that are thought to be important for the binding of insulin to its receptor. ~Our results thus support the hypothesis that, when monomeric insulin is released from the hexamer (or the dimer in our study), the C-terminal end of the monomer (residues B25-B30) is rearranged to allow binding to the insulin receptor. ~The greater flexibility of the C-terminal part of the β chain in the B24 (Phe Gly) mutant is in accord with the NMR results. ~The details of the backbone and side-chain motions are presented. ~The transition between the starting conformation and the more dynamic structure of the monomers is characterized by displacements of the backbone of Phe B25 and Tyr B26; of these, Phe B25 has been implicated in insulin activation.},
	author = {Vincent Zoete and Markus Meuwly and Martin Karplus}
}
@article {118321,
	title = {Dependence of DNA polymerase replication rate on external forces: A model based on molecular dynamics simulations},
	journal = {Biophysical Journal},
	volume = {87},
	year = {2004},
	pages = {1478-1497},
	abstract = {Mol. dynamics simulations are presented for a Thermus aquaticus (Taq) DNA polymerase I complex (consisting of the protein, the primer-template DNA strands, and the incoming nucleotide) subjected to external forces. ~The results obtained with a force applied to the DNA template strand provide insights into the effect of the tension on the activity of the enzyme. ~At forces below 30 pN a local model based on the parameters detd. from the simulations, including the restricted motion of the DNA bases at the active site, yields a replication rate dependence on force in agreement with expt. ~Simulations above 40 pN reveal large conformational changes in the enzyme-bound DNA that may have a role in the force-induced exonucleolysis obsd. exptl.},
	author = {Ioan Andricioaei and Anita Goel and Dudley Herschbach and Martin Karplus}
}
@article {118311,
	title = {Kinetic control of dimer structure formation in amyloid fibrillogenesis},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {101},
	year = {2004},
	pages = {12916-12921},
	abstract = {Amyloid fibril formation involves nonfibrillar oligomeric intermediates, which are important as possible cytotoxic species in neurodegenerative diseases. ~However, their transient nature and polydispersity have made it difficult to identify their formation mechanism or structure. ~We have investigated the dimerization process, the first step in aggregate formation, by multiple mol. dynamics simulations of five β-sheet-forming peptides. ~Contrary to the regular β-sheet structure of the amyloid fibril, the dimers exhibit all possible combinations of β-sheets, with an overall preference for antiparallel arrangements. ~Through statistical anal. of 1,000 dimerization trajectories, each 1 ns in length, we have demonstrated that the obsd. distribution of dimer configurations is kinetically detd.; hydrophobic interactions orient the peptides so as to minimize the solvent accessible surface area, and the dimer structures become trapped in energetically unfavorable conformations. ~Once the hydrophobic contacts are present, the backbone hydrogen bonds form rapidly by a zipper-like mechanism. ~The initial nonequil. structures formed are stable during the 1-ns simulation time for all five peptides at room temp. ~In contrast, at higher temps., where rapid equilibration among different configurations occurs, the distribution follows the global energies. ~The relaxation time of dimers at room temp. was estd. to be longer than the time for diffusional encounters with other oligomers at typical concns. ~These results suggest that kinetic trapping could play a role in the structural evolution of early aggregates in amyloid fibrillogenesis.},
	author = {Wonmuk Hwang and Shuguang Zhang and Roger D. Kamm and Martin Karplus}
}
@article {118306,
	title = {The Role of Sequence and Structure in Protein Folding Kinetics: the Diffusion-Collision Model Applied to Proteins L and G},
	journal = {Structure},
	volume = {12},
	year = {2004},
	pages = {1833-1845},
	abstract = {The diffusion-collision model (DCM) is applied to the folding kinetics of protein L and protein G. ~In the DCM, the two proteins are treated as consisting of two beta-hairpins and one alpha-helix, so that they are isomorphous with the three-helix bundle DCM model. ~In the absence of sequence dependent factors, both proteins would fold in the same way in the DCM, with the coalescence of the N-terminal hairpin and the helix slightly favored over the C-terminal hairpin and the helix because the former are closer together than the latter. ~However, sequence dependent factors make the N-terminal hairpin of protein L and the C-terminal hairpin of protein G more stable in the ensemble of unfolded conformations. ~This difference in the stabilities gives rise to the difference in the calcd. folding behavior, in agreement with expt.},
	author = {Suhail A. Islam and Martin Karplus and David L. Weaver}
}
@article {118301,
	title = {Hidden complexity of free energy surfaces for peptide (protein) folding},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {101},
	year = {2004},
	pages = {14766-14770},
	abstract = {An understanding of the thermodn. and kinetics of protein folding requires a knowledge of the free energy surface governing the motion of the polypeptide chain. ~Because of the many degrees of freedom involved, surfaces projected on only 1 or 2 progress variables are generally used in descriptions of the folding reaction. ~Such projections result in relatively smooth surfaces, but they could mask the complexity of the unprojected surface. ~Here, the authors introduce an approach to det. the actual (unprojected) free energy surface and apply it to a 16-residue peptide, the 2nd β-hairpin of streptococcal protein G, which has been used as a model system for protein folding. ~The surface was represented by a disconnectivity graph calcd. from a long equil. folding-unfolding trajectory. ~The denatured state was found to have multiple low free energy basins. ~Nevertheless, the peptide showed exponential kinetics in folding to the native basin. ~Projected surfaces obtained from the present anal. had a simple form in agreement with other studies of the β-hairpin. ~The hidden complexity found for the β-hairpin surface suggested that the std. funnel picture of protein folding should be revisited.},
	author = {Sergei V. Krivov and Martin Karplus}
}
@article {118296,
	title = {Calculation of the aqueous solvation energy and entropy, as well as free energy, of simple polar solutes},
	journal = {J. Chem. Phys.},
	volume = {121},
	year = {2004},
	pages = {9539-9548},
	abstract = {With the advent of more powerful computers, the question of calcg. thermodn. quantities, such as the energy and the entropy, in solute-solvent systems is revisited. ~The calcn. of these thermodn. quantities was limited in the past by their slow convergence relative to the free energy. ~Using mol. dynamics simulations, the energy, entropy, and free energy of solvation of N-Me acetamide and CH3NH2, as well as their relative values, have been detd. ~Three different methods (the thermodn. perturbation method, the thermodn. integration method, and a finite-difference method) are compared. ~The finite difference method gives the best results and accurate values for the entropy and energy which were obtained using a reasonable amt. to computer time. ~The results suggest that a meaningful thermodn. description of biomol. processes can be realized with present methods and the available computer time.},
	author = {Shunzhou Wan and Roland H. Stote and Martin Karplus}
}
@article {122941,
	title = {Cooperativity in Scapharca Dimeric Hemoglobin: Simulation of Binding Intermediates and Elucidation of the Role of Interfacial Water},
	journal = {Journal of Molecular Biology},
	volume = {326},
	year = {2003},
	pages = {593-606},
	abstract = {Cooperative binding of ligands to proteins can serve to increase their efficiency and to regulate their activity. ~Thus, understanding of the mechanism of cooperativity is one of the central concerns of mol. biol. ~For the tetrameric human Hb (HbA), the cooperative mechanism involves a reasonably well understood combination of tertiary and quaternary changes that occur during the binding process. ~The dimeric Hb of Scapharca (HbI), which is composed of subunits with the same fold as in HbA, is also highly cooperative but the structural changes on ligand binding are small. ~A re-orientation of Phe97 in the binding pocket and changes in the no. of interfacial water moleculess have been implicated in the cooperative mechanism. ~To explore the role of these factors, we have investigated models of partially liganded intermediate states of HbI with mol. dynamics simulation methods. ~Since, unlike HbA, no structures for intermediates are available, they were constructed by combining subunits from the unliganded and liganded dimers. ~Two structurally distinct intermediates were examd., and it was shown that the transition between the two intermediates is directly coupled to the no. of interfacial water mols. ~Further, it was found that there is a well-defined water channel that connects the interface between the subunits to bulk water. ~The bottleneck (gate) of the channel, which can be open or closed, is made of hydrophilic residues. ~The implication of the present results for the cooperative mechanism of HbI is discussed.},
	author = {Yaoqi Zhou and Hongyi Zhou and Martin Karplus}
}
@article {122936,
	title = {Generalized ensembles serve to improve the convergence of free energy simulations},
	journal = {Chem. Phys. Lett.},
	volume = {377},
	year = {2003},
	pages = {633-641},
	abstract = {A novel method for the calcn. of the free energy difference between two states of a mol. system is presented. ~The method, an extension of thermodn. integration, treats the coupling parameter λ as a variable in an extended Hamiltonian formulation and propagates it with the phys. coordinates. ~In the resulting generalized ensemble, the crossing of barriers in the phys. space is enhanced. ~The free energy difference is detd. by integrating the reversible work required to move λ from zero (corresponding to the initial state) to one (corresponding to the final state). ~Examples are presented to illustrate the method.},
	author = {Ryan Bitetti-Putzer and Wei Yang and Martin Karplus}
}
@article {122931,
	title = {A model for the cooperative free energy transduction and kinetics of ATP hydrolysis by F1-ATPase},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {100},
	year = {2003},
	pages = {11339-11344},
	abstract = {Although the binding change mechanism of rotary catalysis by which F1-ATPase hydrolyzes ATP has been supported by equil., kinetic, and structural observations, many questions concerning the function remain unanswered. ~Because of the importance of this enzyme, the search for a full understanding of its mechanism is a key problem in structural biol. ~Making use of the results of free energy simulations and exptl. binding const. measurements, a model is developed for the free energy change during the hydrolysis cycle. ~This model makes possible the development of a kinetic scheme for ATP hydrolysis by F1-ATPase, in which the rate consts. are assocd. with specific configurations of the β subunits. ~An essential new element is that the strong binding site for ADP,Pi is shown to be the βDP site, in contrast to the strong binding site for ATP, which is βTP. ~This result provides a rationale for the rotation of the γ subunit, which induces the cooperativity required for a tri-site binding change mechanism. ~The model explains a series of exptl. data, including the ATP concn. dependence of the rate of hydrolysis and catalytic site occupation for both the Escherichia coli F1-ATPase (EcF1) and Thermophilic Bacillus PS3 F1-ATPase (TF1), which have different behavior.},
	author = {Yi Qin Gao and Wei Yang and Rudolph A. Marcus and Martin Karplus}
}
@article {122926,
	title = {Rare Fluctuations of Native Proteins Sampled by Equilibrium Hydrogen Exchange},
	journal = {Journal of the American Chemical Society},
	volume = {125},
	year = {2003},
	pages = {15686-15687},
	abstract = {We present a method for detg. the ensembles of native protein structures that result from the large fluctuations of low probability revealed by hydrogen-exchange expts. ~The measured protection factors are used to bias Monte Carlo simulations to sample the structures of the exchange competent species. ~The approach is illustrated by its application to the case of α-lactalbumin.},
	author = {Vendruscolo, Michele and Emanuele Paci and Christopher M. Dobson and Martin Karplus}
}
@article {122911,
	title = {Structures and relative free energies of partially folded states of proteins},
	journal = {Proceedings of the National Academy of Sciences of the United States of America},
	volume = {100},
	year = {2003},
	pages = {14817-14821},
	abstract = {The ability of proteins to fold to well defined compact structures is one of the most remarkable examples of the effect of natural selection on biol. mols. ~To understand their properties, including the stability, the mechanism of folding, and the possibilities of misfolding and assocn., it is necessary to know the protein free energy landscape. ~The authors use NMR data as restraints in a Monte Carlo sampling procedure to det. the ensemble of structures populated by human α-lactalbumin in the presence of increasing concns. of urea. ~The ensembles of structures that represent the partially folded states of the protein show that two structural cores, corresponding to portions of the α and β domains of the native protein, are preserved even when the native-like interactions that define their existence are substantially weakened. ~Anal. of the network of residual contacts reveals the presence of a complex interface region between the two structural cores and indicates that the development of specific interactions within this interface is the key step in achieving the native structure. ~The relative probabilities of the conformations detd. from the NMR data are used to construct a coarse-grained free energy landscape for α-lactalbumin in the absence of urea. ~The form of the landscape, together with the existence of distinct cores, supports the concept that robustness and modularity are the properties that make possible the folding of complex proteins.},
	author = {Vendruscolo, Michele and Emanuele Paci and Martin Karplus and Christopher M. Dobson}
}
@article {119221,
	title = {Protein-ligand binding free energy estimation using molecular mechanics and continuum electrostatics. Application to HIV-1 protease inhibitors},
	journal = {Journal of Computer-Aided Molecular Design},
	volume = {17},
	year = {2003},
	pages = {861-880},
	abstract = {A method is proposed for the estn. of abs. binding free energy of interaction between proteins and ligands. ~Conformational sampling of the protein-ligand complex is performed by mol. dynamics (MD) in vacuo and the solvent effect is calcd. a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory. ~The binding free energy is written as a linear combination of the buried surface upon complexation, SASbur, the electrostatic interaction energy between the ligand and the protein, Eelec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, ΔGsolv. ~The method uses the buried surface upon complexation to account for the nonpolar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy. ~The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure. ~A correlation coeff. of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol. ~When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calcd. binding free energy and the exptl. pIC50 without reparametrization.},
	author = {Vincent Zoete and Olivier Michielin and Martin Karplus}
}
@article {28756,
	title = {Uracil-DNA Glycosylase Acts by Substrate Autocatalysis},
	journal = {Nature},
	volume = {413},
	year = {2001},
	pages = {752-755},
	author = {A. R. Dinner and G. M. Blackburn and M. Karplus}
}
@article {28751,
	title = {Triosephosphate Isomerase: A Theoretical Comparison of Alternative Pathways},
	journal = {J. Am. Chem. Soc.},
	volume = {123},
	year = {2001},
	pages = {2284-2290},
	author = {Q. Cui and M. Karplus}
}
@article {28746,
	title = {A Dynamic Model for the Allosteric Mechanism of GroEL},
	journal = {J. Mol. Biol.},
	volume = {302},
	year = {2000},
	pages = {303-313},
	author = {J. Ma and P. B. Sigler and Z. Xu and M. Karplus.}
}
@article {28741,
	title = {Understanding Protein Folding via Free-Energy Surfaces from Theory and Experiment},
	journal = {TiBS},
	volume = {25},
	year = {2000},
	pages = {331-339},
	author = {A. R. Dinner and A. Sali and L. J. Smith and C. M. Dobson and M. Karplus}
}
@article {28726,
	title = {Aspects of Protein Reaction Dynamics: Deviations from Simple Behavior},
	journal = {J. Phys. Chem. B },
	volume = {104},
	year = {2000},
	pages = {11-27 },
	author = {M. Karplus}
}
