Study of the insulin dimerization: Binding free energy calculations and per-residue free-energy decomposition

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.