Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions†
Drug resistance of mutations in HIV-1 protease (PR) badly reduce the efficiency of the current inhibitors in clinical treatments of AIDS. In this work, molecular dynamics (MD) simulations coupled with binding free energy predictions were performed to study drug-resistant mechanisms of three mutations V32I, I47V and V82I on inhibitors saquinavir (SQV), amprenavir (APV) and darunavir (DRV). The results from dynamics analyses suggest that the side-chain alternations of three mutated residues produce important effects on distances between the flaps and catalytic sites of HIV-1 protease and the dihedral angle Chi1 of the mutated residues and I50/I50′. These conformational changes induce significant decreases in the occupancy of most hydrogen bonds and the interaction enthalpy of key residues with inhibitors in the mutated complexes, especially for the flap residues I50/I50′, which provide the main contributions to drug resistance of mutations toward these inhibitors. The results of binding free energy calculations show that the decrease in van der Waals interaction of inhibitors with the mutated PR relative to the wild-type (WT) PR mostly drive drug resistance of mutations toward inhibitors. We expect that this study can theoretically contribute significant guidance to designs of potent inhibitors targeting HIV-1 protease.