Exploring drug-resistant mechanisms of I84V mutation in HIV-1 protease toward different inhibitors by thermodynamics integration and solvated interaction energy method

Highlights: • This work aims at probing the drug resistance mechanism of I84V mutation on four inhibitors O17, G3G, O65 and ROC by using molecular dynamics simulations and binding free energy calculations. • The results prove that the alternation of the position of key residues relative to the hydrophobic groups of inhibitors induced by mutations contributes to the decrease in van der Waals interactions of inhibitors with mutated PRs, which is the main origin of drug resistance. • The results will provide valuable information for designing the potent inhibitors targeting the drug resistance of HIV-1 PR mutations. I84V mutation in HIV-1 protease (PR) has produced drug resistance on multiple inhibitors. Thermodynamic integration (TI), solvated interaction energy (SIE) and dynamic analysis were applied to comparatively probe drug-resistant mechanisms of I84V mutation toward four inhibitors. Dynamic analysis suggests that in the I84V mutants the flaps of PR are more flexible and domains near the flaps of PR and residues 84/84′ also change obviously. Binding free energy predictions show I84V mutation mainly drive the decrease in van der Waals interactions of inhibitors with PR. This study is expected to provide theoretical helps for designs of potent inhibitors targeting HIV-1 protease.