Thermodynamics and biophysical basis of drug resistance in HIV-1 protease via multiscale simulations

Abstract

Drug resistance due to mutation has sharply limited the effectiveness of HIV-1 protease inhibitors in AIDS therapy. It is critically important to understand the molecular basis of drug resistance for designing new drugs. Elucidating the dynamic nature and thermodynamic basis of binding of drugs to wild-type and mutant variants of protease could be insightful, for the development of resistance-evading drugs. In this study, we have conducted molecular dynamics simulations in combination with the free energy calculation for elucidating the mechanism of binding of the inhibitor TMC-126 to HIV-1 protease. Five mutant variants (A28S, V32I, M46L, I50V, and MDR20) and HIV-2 protease are also considered. The popular and widely used Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method is utilized to calculate the free energy of binding and the normal mode analysis is performed for estimating the entropic contribution to the binding free energy.From our study it is observed that for all cases, the binding is mainly driven by the van der Waals interactions. Furthermore, it is observed that the intermolecular electrostatic interactions and the nonpolar solvation free energy also contribute favourably to the binding free energy. However, the intermolecular electrostatic interaction is over-compensated by the unfavorable polar solvation free energy.The inhibitor is found to be losing its potency against all five mutant variants. A significant decrease in the binding free energy is observed for A28S and V32I mutations. Our study suggests that the mutation-induced drug resistance arises mainly because of decrease in intermolecular electrostatic interactions compared to the wild-type. Over all, the current study elucidates the biophysical basis of drug resistance and may help in designing new drugs that can be effective against mutant variants.