Kinetic control of dimer structure formation in amyloid fibrillogenesis

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.