Exploring molecular mechanism of allosteric inhibitor to relieve drug resistance of multiple mutations in HIV-1 protease by enhanced conformational sampling.

Recently, allosteric regulations of HIV-1 protease (PR) are suggested as a promising approach to relieve drug resistance of mutations toward inhibitors targeting the active site of PR. Replica-exchange molecular dynamics (REMD) simulations and normal mode analysis (NMA) are integrated to enhance conformational sampling of PR. Molecular mechanics generalized Born surface area (MM-GBSA) method was applied to calculate binding free energies of three inhibitors APV, DRV, and NIT to the wild-type (WT) and multidrug resistance (MDR) PRs. The results suggest that binding free energies of APV and DRV are decreased in the MDR PR relative to the WT PR, suggesting drug resistance of mutations on these two inhibitors. However, the binding ability of the allosteric inhibitor NIT is not impaired in the MDR PR. In addition, internal dynamics analysis based on REMD simulations proves that mutations hardly produce obvious effect on the conformation of the MDR PR in comparison to the WT PR. Scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with residues of PRs on the concatenated trajectories of REMD demonstrates that mutations change the symmetric interaction networks of APV and DRV with PR, but do not generate obvious influence on the asymmetric interaction network of NIT with PR. In summary, allosteric inhibitor NIT can adapt the MDR PR better than those inhibitors toward the active site of PR, thus allosteric inhibitors of PR may be a possible channel to overcome drug resistance of PR.