title: Study of the insulin dimerization: binding free energy calculations and per-residue free energy decomposition.
abstract: A calculation of the binding free energy for the dimerization of insulin has been performed using the molecular mechanics-generalized Born surface area approach. The calculated absolute binding free energy is -11.9 kcal/mol, in approximate agreement with the experimental 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 decomposition of the binding free energy has been performed to identify the residues contributing most to the self association 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 decomposition on a per-residue basis is in agreement with experimental alanine scanning data. The results obtained from a single trajectory (i.e., the dimer trajectory is also used for the monomer analysis) and 2 trajectories (i.e., separate trajectories are used for the monomer and dimer) are similar.
authors.affiliation: Laboratoire de Chimie Biophysique, ISIS/Université Louis Pasteur, Strasbourg Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Markus
authors.initials: M
authors.lastname: Meuwly
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
mesh_terms: D018360:Crystallography, X-Ray; D019281:Dimerization; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D007328:Insulin