鹅膏毒肽类毒素与RNA聚合酶II相互作用的理论研究

项目名称： 鹅膏毒肽类毒素与RNA聚合酶II相互作用的理论研究

项目编号： No.31200048

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 微生物学、植物学

项目作者： 张蕊

作者单位： 鲁东大学

项目金额： 23万元

中文摘要： 鹅膏毒肽能够专一性抑制RNA聚合酶Ⅱ的活性，这使其在分子生物学、医学生物学、发育生物学等领域具有重要的研究意义。由于很难获得实验用量的活性鹅膏毒肽样品，采用理论方法研究鹅膏毒肽与RNA聚合酶II的相互作用机制具有独特的优势。该项目在获得鹅膏毒肽及RNA聚合酶II合理构型的基础上，开展分子对接、分子动力学及QM/MM的研究，得到鹅膏毒肽与RNA聚合酶Ⅱ相互作用的结合位点、结合自由能、结合稳定性、结合常数和构象变化等信息，寻找鹅膏毒肽中导致机体中毒的关键基团以及鹅膏毒肽的毒性与结构间的内在关系，进而从分子水平上获得中毒机理，揭示鹅膏毒肽与RNA聚合酶Ⅱ的相互作用机制；在以上研究的基础上，采用3D-QSAR的药物设计方法(包括CoMFA和CoMSIA方法)，对类鹅膏毒肽分子的立体场、静电场、疏水场、氢键场等性质与其生物活性相关联，设计获得理想的先导化合物，为类鹅膏毒肽药物开发提供理论支持。

中文关键词： 鹅膏毒肽；RNA聚合酶II；分子模拟；分子动力学；相互作用

英文摘要： Amanitins, as a kind of peptide toxin, can specially inhibit the activity of RNA polymerase II, which makes them have great value in molecular biology, medical biology, developmental biology，etc. However, it is very difficult to get enough amanitins for experimental study. Thus,theoretical methods have particular advantages to study the interaction mechanism between amanitins and RNA polymerase II. In this study, on the basis of the crystal structure of RNA polymerase II and the reasonable three-dimensional structures of amanitins, molecular docking, molecular dynamics and QM/MM(quantum mechanics/molecular mechanics ) methods can be carried out to study the mechanism between RNA polymerase II and amanitins. We can get many important information including the binding site, binding free energy, binding stability, binding constant, conformational change of amanitins and RNA polymerase II, etc. According to these information, we can find the key substituent of amanitins induced the poisoning, get the interrelationship between the toxity and the structure, and on molecular level, deeply reveal the poisioning mechanism and the interaction mechanism between amanitins and RNA polymerase II. Further, based on the interaction mechanism of amanitins and RNA polymerase II, using the 3D-QSAR(three-Dimensional Quantitative St

英文关键词： Amanitins；RNA polymerase II；molecular simulation；molecular dynamics；interaction