计算方法研究HIV-1蛋白酶及其变异与小分子GRL-0519的相互作用
发布时间：2018-10-14 09:16
【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.
[Abstract]:The spread of HIV in the world seriously threatens people's physical and mental health. The mutation of HIV-1 protease residues seriously weakens the therapeutic effect of drugs. In order to study the effect of residue variant D30NNtI54M and V82A on protease binding inhibitor GRL-0519, four 30 ns molecular dynamics (MD) simulations were carried out, and the binding energies of protease and inhibitor were calculated by means of dissolution mutual free energy (SIE) method. The results showed that the polar interaction was not conducive to the protease binding inhibitor, but had a weak contribution to the polar interaction of the wild type protease (WT), and the polar interaction was the main reason for the resistance of the residue variant. The calculated total binding energy is consistent with the experimental data. In order to explain the contribution of each residue to drug resistance, the van der Waals interaction energy of each residue with small molecules was calculated by molecular force field method, and the hydrogen bond formed between inhibitor and protease was analyzed. Van der Waals interaction analysis showed that the V82A residue variation had little effect on the binding model, and there were 6 residues in the protease with more than 0.4 kcal/mol,I54M residue variation compared with the Van der Waals contribution with 5 residues in WT,D30N. The hydrogen bond analysis shows that several hydrogen bonds are lost in the D30N and I54M mutations, and the results of van der Waals interaction and hydrogen bond analysis are in agreement with the results calculated by SIE. The results provide theoretical guidance for the design of new and more effective inhibitors against HIV-1 protease mutation.
【作者单位】： 德州学院物理与电子信息学院;德州学院山东省生物物理重点实验室;
【基金】：国家自然科学基金(11447004,61671107) 山东省自然科学基金(ZR2014JL006) 山东省泰山学者基金资助项目~~
【分类号】：R373
，
本文编号：2270033
[Abstract]:The spread of HIV in the world seriously threatens people's physical and mental health. The mutation of HIV-1 protease residues seriously weakens the therapeutic effect of drugs. In order to study the effect of residue variant D30NNtI54M and V82A on protease binding inhibitor GRL-0519, four 30 ns molecular dynamics (MD) simulations were carried out, and the binding energies of protease and inhibitor were calculated by means of dissolution mutual free energy (SIE) method. The results showed that the polar interaction was not conducive to the protease binding inhibitor, but had a weak contribution to the polar interaction of the wild type protease (WT), and the polar interaction was the main reason for the resistance of the residue variant. The calculated total binding energy is consistent with the experimental data. In order to explain the contribution of each residue to drug resistance, the van der Waals interaction energy of each residue with small molecules was calculated by molecular force field method, and the hydrogen bond formed between inhibitor and protease was analyzed. Van der Waals interaction analysis showed that the V82A residue variation had little effect on the binding model, and there were 6 residues in the protease with more than 0.4 kcal/mol,I54M residue variation compared with the Van der Waals contribution with 5 residues in WT,D30N. The hydrogen bond analysis shows that several hydrogen bonds are lost in the D30N and I54M mutations, and the results of van der Waals interaction and hydrogen bond analysis are in agreement with the results calculated by SIE. The results provide theoretical guidance for the design of new and more effective inhibitors against HIV-1 protease mutation.
【作者单位】： 德州学院物理与电子信息学院;德州学院山东省生物物理重点实验室;
【基金】：国家自然科学基金(11447004,61671107) 山东省自然科学基金(ZR2014JL006) 山东省泰山学者基金资助项目~~
【分类号】：R373
，
本文编号：2270033
本文链接：https://www.wllwen.com/xiyixuelunwen/2270033.html
最近更新
教材专著
