【摘要】 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.更多还原

【Abstract】 The spread of HIV-1 in the world is a serious threat to people’s physical and mental health. Residue mutation of HIV-1 protease seriously weakened the effect of drug treatment. In order to study the effects of mutations D30 N, I54 M and V82 A on the interaction between protease and the inhibitor GRL-0519, we carried out four 30 ns molecular dynamics(MD) simulations combined with the solvated interaction energy(SIE) method to calculate the binding free energies of protease and inhibitor. The results show that polar interactions are unfavorable for the mutated protease bonding to the inhibitor, and slightly favorable for WT, the polar interactions are the main driven force for the drug resistance. The calculated total free energies are consistent with the experimental data. In order to show the contribution of each residue to drug resistance, the van der Walls energies of each residue were calculated by the molecular force field method, the hydrogen bonds between inhibitor and protease were also analyzed. The van der Walls analysis implies that the V82 A has smaller influence on the binding model. There are five residues with van der Waals contribution larger than 0.4 kcal/mol for D30 N, and six residues for I54 M. The hydrogen bond analysis suggests that D30 N and I54 M lost several hydrogen bonds relative to in WT. The result was in accordance with the SIE results. Our study provides theoretical guidance for the design of new and more potent inhibitors against HIV-1 protease variants.更多还原