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艾滋病病毒在世界范围内的传播,严重地威胁到人们的身心健康.HIV-1蛋白酶的残基变异严重地削弱了药物的治疗效果.为了研究残基变异D30N、I54M和V82A对蛋白酶结合抑制剂GRL-0519的影响,本研究进行了4个30 ns的分子动力学(MD)模拟,并采用溶解相互自由能(SIE)方法计算了蛋白酶和抑制剂的结合能.计算结果表明,极性相互作用不利于变异的蛋白酶结合抑制剂,而对于野生型的蛋白酶(WT),极性相互作用有微弱的贡献,极性相互作用是残基变异抗药性的主要原因,计算得到的总结合能与实验的数据一致.为了说明每个残基在抗药性中的贡献,采用分子力场的方法计算了每一个残基与小分子作用的范德华作用能,并分析了抑制剂与蛋白酶形成的氢键.范德华作用分析表明,V82A残基变异对结合模式的影响较小,相对于WT,D30N有5个残基的范德华贡献差异大于0.4 kcal/mol,I54M残基变异的蛋白酶有6个残基.氢键的分析说明,D30N和I54M变异丢失了几个氢键;范德华作用和氢键的分析结果与SIE的计算结果一致.研究结果为设计新的更有效的抗HIV-1蛋白酶变异的抑制剂提供了理论指导.
HIV transmission worldwide, a serious threat to people’s physical and mental health.HIV-1 protease residues severely impaired the therapeutic effect of the drug.In order to study the residue mutations D30N, I54M and V82A protease binding inhibitor GRL-0519, four 30-ns molecular dynamics (MD) simulations were performed in this study, and the binding energy of protease and inhibitor was calculated by the method of Dissolved Mutual Free Energy (SIE). The calculated results show that the polarities of each other The effect is not conducive to mutation of the protease-binding inhibitor, and for wild-type protease (WT), polar interactions have a weak contribution, polar interactions is the main reason for residue mutation resistance, the calculated total binding energy and To demonstrate the contribution of each residue in drug resistance, the van der Waal’s acting on the interaction of each residue with the small molecule was calculated using the molecular force field and the hydrogen bond between the inhibitor and the protease was analyzed Van der Waals effect analysis showed that V82A residue variation had less effect on the binding mode, compared with WT, Van der Waals’ contribution of 5 residues at D30N was greater than 0.4 kcal / mol with I54M residue mutation The enzyme has 6 residues.The analysis of hydrogen bond shows that there are several hydrogen bonds lost in D30N and I54M variation.The results of van der Waals interaction and hydrogen bond are consistent with those of SIE.The results are as follows: -1 protease variant inhibitors provide theoretical guidance.