Calculating the absolute binding free energy of the insulin dimer in an explicit solvent.

Insulin is a significant hormone in the regulation of glucose level in the blood. Its monomers bind to each other to form dimers or hexamers through a complex process. To study the binding of the insulin dimer, we first calculate its absolute binding free energy by the steered molecular dynamics method and the confinement method based on a fictitious thermodynamic cycle. After considering some special correction terms, the final calculated binding free energy at 298 K is -8.97 ± 1.41 kcal mol, which is close to the experimental value of -7.2 ± 0.8 kcal mol. Furthermore, we discuss the important residue-residue interactions between the insulin monomers, including hydrophobic interactions, π-π interactions and hydrogen bond interactions. The analysis reveals five key residues, Vla, Tyr, Phe, Phe, and Tyr, for the dimerization of the insulin. We also perform MM-PBSA calculations for the wild-type dimer and some mutants and study the roles of the key residues by the change of the binding energy of the insulin dimer.