中文摘要：

HIV-1复制需要HIV-1整合酶将其环状DNA整合进宿主DNA中,这其中包括2个重要反应,即“3′-加工”和“链转移”,两者均由HIV-1整合酶催化完成.阻断其中的任一反应,都能达到抑制HIV-1复制的目的.因此,了解HIV-1整合酶的完整结构和聚合状态,对深入探讨其作用机理及设计新型抑制剂具有重要的指导作用.然而,迄今为止仅有HIV-1整合酶单独结构域的晶体结构可供参考,而其全酶晶体结构尚未获得解析.本研究利用分子模拟技术,通过蛋白质-蛋白质/DNA分子对接、动力学模拟等方法,构建了全长整合酶四聚体的结构模型、HIV-1DNA与整合酶复合物的结构模型,进一步从理论上证实HIV-1整合酶是以四聚体形态发挥催化作用,明确“3′-加工”和“链转移”在HIV-1整合酶上的催化位点.同时,通过与作用机理相似的细菌转座子Tn5转座酶等的结构比对,推测HIV-1整合酶的核心结构域中应有第2个Mg^2＋存在,其位置螯合于Asp64与Glu152之间.在HIV-1整合酶结构研究的基础上,有望进一步设计出新的抗艾滋病药物.

英文摘要：

The replication of the HIV-1 requires the integration of the cyclic DNA into the host DNA by the HIV-1 integrase, which includes two important reactions, 3＇-processing and strand transfer, both completed by the HIV-1 integrase. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. Therefore, an in-depth understanding of the complete structure and assembly state of the HIV-1 integrase provides significant directions for insightful investigation of the mechanism and the inhibitor design against this integrase. However, there are crystal structures of a single domain of the HIV-1 integrase so far, whereas the crystal structure of the entire enzyme is not yet determined. This research utilized molecular modeling techniques, including protein-protein/DNA molecular docking and dynamic simulation methods, to construct the structure model of the integrase tetramer of full length and its complex with the HIV-1 DNA. The results further proved in theory that the HIV-1 integrase catalyzes reactions in a tetramer state and verified the catalytic sites of the HIV-1 integrase during 3′-processing and strand transfer. Meanwhile, the structural comparison between the HIV-1 integrase and Tn5 transposase of similar mechanism predicted the existence of a second Mg^2＋ in the core domain of the HIV-1 integrase, chelated between Asp64 and Glu152. Based on this research of the HIV-1 integrase structure, drug design against AIDS will be facilitated and hopefully enhanced to a considerable extent.