分子动力学模拟研究质子化态在HIV-1 Protease-Indinavir复合物中的作用

Molecular Dynamics Simulations on the Role of Protonation States in HIV-1 Protease-Indinavir Complex

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.

The protonation state of Asp25/Asp25＇ in Protease-Indinavir （PR-IDV） complex is important for HIV-1 protease to study the binding mechanism and the drug resistance induced by the mutation in theory. The 5 ns molecular dynamic simulations have been performed for six possible protonation states, the influences on dynamics behavior and structure caused by different protonation states analyzed, and relative binding free energies calculated using the molecular mechanics/Possion-Boltzman surface area （MM-PBSA） method. The results show that the protonation state of OD2 from Asp25 in chain A is the most possible. The hydrogen bonds between the water molecule that plays a medium role and the PR-IDV complex were also analyzed, and the results show that the different states have not obvious influences on the medium role, which is different from our previous result on PR-BEA369 complex. It was expected that this study could provide a significative help for the high affinity inhibitor design and the mutation induced drug resistance research.