Simulation Study Of The Insulin Dimer By Steered Molecular Dynamics

For almost a century,the insulin has demonstrated to be a key drug for treating the diabetes.Under the physiological conditions,regulating the blood glucose is a complex process.It involves the dissociation of insulin hexamer and dimer,and the binding of insulin monomer to receptor.However,due to the unclear mechanisms,there are still many challenges in developing efficient insulin analogues.Insulin must rapidly regulate the blood glucose after subcutaneous injection.To achieve this goal,people need to significantly reduce the affinity of insulin dimer,but there are still many difficulties in calculating the binding free energy of protein-protein complex.On the basis of previous studies,we propose a new free energy calculation method to calculate protein-protein binding free energy.We compute the absolute binding free energy of insulin dimer by the thermodynamic cycle and the steered molecular dynamics（SMD）method.After considering many correction terms,the final result at 298 K is-8.97±1.41 kcal/mol,which is close to the experimental value of-7.2±0.8 kcal/mol.It suggests our approach is feasible.Besides,we also compare the current work with the previous researches.It shows that thermodynamic integration（TI）is the most accurate method,our computational accuracy is slightly lower than TI,the worst result is MM-PB（GB）SA.It may be because MM-PB（GB）SA indirectly computes the free energy.Because the role of key residues in the process of insulin monomer binding to dimer is not completely clear,we also calculate the important residue-residue interactions between the insulin monomers,including hydrophobic interaction,π-πinteraction and hydrogen bond interaction.These interactions involve five key residues Vla^B12,Tyr^B16,Phe^B24,Phe^B25 and Tyr^B26.Finally,we use MM-PBSA to compute relative binding free energy between wild-type（WT）dimer and mutants.The results show that MM-PBSA is practical in calculating the relative binding free energy.Moreover,we compare the secondary structures among them,and find only the secondary structures of mutant Phe^B24Ala displays a distinct change.