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I型人体免疫缺陷病毒(HIV-1)蛋白酶中Asp25/Asp25’的质子化对于理论研究HIV-1蛋白酶和抑制剂的作用机制以及氨基酸变异对抗药性的影响有重要意义.分别对Protease-Indinavir(PR-IDV)复合物的六种可能的质子化态进行了5ns的分子动力学模拟,分析了不同状态对动力学特征和结构的影响,用molecular mechanics/Possion-Boltzman surfacearea(MM-PBSA)方法计算了PR和IDV在各种状态下的结合自由能.计算结果说明A链Asp25的OD2的质子化是最为可能的状态.对PR-IDV复合物中起到媒介作用的水分子与PR-IDV复合物形成的氢键进行了分析,分析结果说明不同的质子化态对水分子在PR-IDV复合物中所起的媒介作用没有影响,这一结果与我们先前对PR-BEA369复合物的研究不同.我们的研究结果为更高效的PR抑制剂的设计以及PR氨基酸变异对药物抗药性的研究提供了理论上的指导.
Protonation of Asp25 / Asp25 ’in type I human immunodeficiency virus (HIV-1) protease plays an important role in the theoretical study of the mechanism of action of HIV-1 protease and inhibitor and the effect of amino acid mutation on drug resistance.Protease-Indinavir PR-IDV) complexes were subjected to 5-ns molecular dynamics simulations. The effects of different states on the kinetic characteristics and structures were analyzed. The molecular mechanics / Possion-Boltzman surfacearea (MM-PBSA) method The free energy of binding of PR and IDV in various states was calculated.The results showed that the protonation of OD2 of Asp25 in A chain was the most probable state.The interaction of water molecules and PR-IDV The hydrogen bonds formed by the complexes were analyzed and the results showed that different protonation states had no effect on the mediator effect of water molecules in the PR-IDV complex. This result is consistent with our previous study of the PR-BEA369 complex Different.The results of our study provide theoretical guidance for the design of more efficient PR inhibitors and the research on the drug resistance of PR amino acid mutation.