PFV整合酶受体与配体识别的计算模型研究

项目名称： PFV整合酶受体与配体识别的计算模型研究

项目编号： No.11247018

项目类型： 专项基金项目

立项/批准年度： 2013

项目学科： 物理学II

项目作者： 胡建平

作者单位： 乐山师范学院

项目金额： 20万元

中文摘要： 整合酶将人类免疫缺陷病毒（HIV）DNA整合到宿主DNA中，是抗艾滋病新药研发的重要靶点，而异吲哚化合物能有效抑制整合酶活性。原核泡沫病毒（PFV）整合酶的结构与HIV整合酶高度同源，并含有后者所缺乏的DNA及Raltegravir药物的结合信息。PFV 整合酶与DNA及抑制剂的复合物结构复杂，在发挥催化功能时，构象有大幅变化，建立PFV 整合酶受体与配体识别的计算模型十分必要。本项目旨在通过计算方法的研究，预测PFV整合酶与DNA及抑制剂的结合模式，获得相互作用的关键残基和碱基；分析构象变化、抗药性及结合自由能等有用信息，建立抗艾滋病药物筛选平台。结合课题组前期研究基础，发展适于PFV 整合酶的分子对接、粗粒化弹性网络模型和密度泛函理论方法，揭示酶功能性慢运动模式以及镁离子的金属效应。该项目不仅在复杂体系识别的计算方法学上进行了有益探索，而且对基于整合酶结构的抗艾滋病药物设计提供帮助。

中文关键词： 整合酶；结合模式；构象变化；识别；计算模型

英文摘要： Integrase (IN) aids the integration of human immunodeficiency virus (HIV) DNA into the host DNA, and is an important target for designing and developing the novel anti-AIDS drug. Isoindol compounds can effectively inhibit the activity of IN. The structure of prototyp foamy virus (PFV) IN has a high homology with HIV IN, and has the binding information of DNA and Raltegravir drug lacked in the latter system. The structure of PFV IN with DNA and inhibitor is very complex, and there is a large conformational change when the system exerts its catalyzing function.Thus, it is nessary to establish the computing model for the recognition between PFV IN receptor and its ligands.Through the study on the computing methods, the project aims at predicting the bingding modes of PFV IN with DNA and inhibitors, obtaining the key residues and bases for the interactions, analyzing the useful information about conformational change, drug resistance and binding free energy, building the platform of anti-AIDS drug screening. From the previous studies of our research group, we will develop molecular docking, coarse-grained elastic network model and density functional theory methods fit for PFV IN system. Finally, the funcitonal slow motion mode for the enzyme and the metal effect of magnesium ions are explained. The project not only

英文关键词： integrase；binding mode；conformational change；recognition；computing model