Abstract
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−1, which is close to the experimental value of −7.2 ± 0.8 kcal mol−1. 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, VlaB12, TyrB16, PheB24, PheB25, and TyrB26, 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.
Highlights
Insulin is a crucial hormone which regulates glucose level in blood
The results show the importance of the p–p interaction, hydrophobic interaction and the hydrogen bond interaction in the dimerization process
At 298 K, concentration difference spectroscopy experiment presents that the insulin dimer's binding free energy is À7.2 Æ 0.8 kcal molÀ1 and the isothermal titration microcalorimetry (ITC) dilution experiment gives its dissociation free energy 6.88 Æ 0.03 kcal molÀ1.42 These studies suggest that both of the insulin dimerization and dissociation are enthalpy control
Summary
Insulin is a crucial hormone which regulates glucose level in blood. It is stored in the pancreas as a hexamer, and it only shows the biological activity in a monomeric form.[1,2] The whole process follows three steps in the physiological conditions. For the rst problem, despite many studies having been done in this eld,[4,5,6,7,8] the real binding mechanism of the insulin monomers is still unclear.[9] In order to solve the second problem, some fast-acting insulin analogues with low affinities have been exploited, such as lispro insulin (LysB28, ProB29),[10] and insulin glulisine (LysB3, GluB29).[11]
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