COMPUTER SIMULATIONS OF PROTEIN STRUCTURE AND DYNAMICS

本提案中所述的研究重点是开发和 应用计算方法研究 蛋白质的结构、动力学和功能。 计算机模拟提供了 最详细的理论方法可用于研究蛋白质在一个 分子水平。 本提案在下一个资助期内的目标 在两个方面：一. 结构与动力相结合 信息从解决方案NMR和计算机模拟，和II. 研究 蛋白质的溶剂化和溶剂对静电的影响， 计算机仿真 第一个目标是开发必要的计算工具， 来提取最结构和动态的信息， 快速推进的蛋白质二维核磁共振实验。 为了不断 与实验NMR组合作，结构和动力学研究 将在包括防御素多肽的几种系统上进行， 芋螺毒素和α-乳白蛋白。 第二个目标是需要对以下方面有一个更基本的了解： 分子力如何决定蛋白质结构以及结构变化 从而产生特定的功能。 其中最重要的力量， 被认为是这样的蛋白质功能，如结合，催化， 运输，是静电相互作用。 正在制定方法， 改进这些相互作用在微观模拟中的处理方式 基于反应场模型的使用。 这些方法将 应用于模拟双电荷酸中的pKa位移等问题 和两性离子，分析溶剂化对α-螺旋偶极子的影响， 绘制电子转移蛋白天青蛋白的表面特性。 这项研究的健康相关性是在更准确的建模， 蛋白质在溶液中的性质和使用改进的 研究蛋白质结构和功能的计算工具， 基于建模的合理药物设计策略。

The research described in this proposal focuses on the development and application of computational methods for studying the relationship between structure, dynamics and function of proteins. Computer simulations provide the most detailed theoretical approach available to study proteins at a molecular level. The goals of this proposal during the next grant period are in two areas: I. the integration of structure with dynamics information from solution NMR and computer simulations, and II. the study of the solvation of proteins and solvent effects on electrostatics by computer simulation. The first goal addresses the need to develop computational tools necessary to extract the most structural and dynamical information contained in rapidly advancing 2D-NMR experiments on proteins. In a continuing collaboration with experimental NMR groups, structure and dynamics studies will be carried out on several systems including defensin polypeptides and conotoxins, and the protein alpha-lactalbumin. The second goal addresses the need to develop a more basic understanding of how molecular forces determine protein structure and the structural changes which give rise to specific functions. Among the most important forces to be considered for such protein functions as binding, catalysis, and transport, are electrostatic interactions. Methods are being developed for improving the way these interactions are treated in microscopic simulations based on the use of the reaction field model. These methods will be applied to such problems as simulating pKa shifts in doubly charged acids and zwitterions, analyzing solvation effects on the alpha-helix dipole, and to mapping the surface properties of Azurin, an electron transfer protein. The health relatedness of this research is in the more accurate modeling of the properties of proteins in solution and the use of improved computational tools for studying protein structure and function with rational drug design strategies based on modeling.