多尺度模拟集成小角散射数据研究蛋白质构象变化的方法

项目名称： 多尺度模拟集成小角散射数据研究蛋白质构象变化的方法

项目编号： No.31270760

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 张志勇

作者单位： 中国科学技术大学

项目金额： 60万元

中文摘要： 多结构域蛋白和蛋白复合物通常具有很大的柔性，存在着大尺度的构象变化，并与其生物学功能密切相关。X射线小角散射是近年来快速发展的结构生物学技术，它非常适合于研究高度柔性的多结构域蛋白和蛋白复合物，提供其在溶液中的低分辨率结构信息。本项目的研究重点是发展蛋白构象空间高效采样的多尺度模拟方法，并集成小角散射数据，分析蛋白在溶液中构象状态的分布及指导蛋白构象空间采样。通过模拟噬菌体T4溶菌酶的结构域运动对这些方法进行检验，进而研究人粘着斑蛋白vinculin及其与CAP蛋白羧基端串联SH3结构域所形成复合物的构象变化，显示方法的应用潜力并进一步完善。多尺度模拟集成小角散射数据使我们能更准确地模拟多结构域蛋白和蛋白复合物的大尺度构象变化，有助于深入探讨构象变化和蛋白功能的关系，从而推动计算机模拟在结构生物学中的应用。

中文关键词： 多尺度模拟；X射线小角散射；分子动力学模拟；增强采样技术；粗粒化模型

英文摘要： Many multidomain proteins and protein complexes are very mobile, which involve large-scale conformational dynamics in solution. These kinds of proteins are difficult to study by high-resolution methods, such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, due to their high flexibility and large size. Small-angle X-ray scattering (SAXS) is thus a complementary method to those high-resolution techniques, which provides low-resolution structural characterization of proteins in solution. Despite its low-resolution nature, information of protein dynamics is encoded within the one-dimensional SAXS profile. This project will develop advanced computational methods for multiscale simulations combining SAXS data, in order to investigate large-scale conformational changes in multidomain proteins and protein complexes. Various multiscale simulations at atomistic or coarse-grained level, together with enhanced sampling techniques, will be performed to extensively explore protein conformational space. SAXS data can be used to post-analyze the conformational ensemble generated by atomistic or coarse-grained simulations, and then determine the relative population of typical conformational states in the protein. It can also serve as a moderate constraint in these simulations to guide the conformationa

英文关键词： multi-scale simulations；small-angle X-ray scattering；molecular dynamics simulations；enhanced sampling techniques；coarse-grained models