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.

HIV-1蛋白酶（PR）中的I84V突变已对多种抑制剂产生耐药性。应用热力学积分（TI），溶剂化相互作用能（SIE）和动力学分析来比较地探究针对四种抑制剂的I84V突变的耐药机制。动态分析表明，在I84V突变体中，PR的皮瓣更加灵活，PR的皮瓣附近的结构域和残基84/84'也发生了明显变化。结合自由能的预测表明，I84V突变主要驱动抑制剂与PR的范德华相互作用的降低。预期该研究将为设计针对HIV-1蛋白酶的有效抑制剂提供理论帮助。