Application of Molecular Dynamics Simulations to Conformational Stability of Peptides and Proteins

分子动力学模拟在肽和蛋白质构象稳定性中的应用

• 批准号: 9314854
• 负责人: Jan Hermans
• 金额: $ 30.75万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9314854&HistoricalAwards=false
• 关键词: Application; Molecular; Dynamics; Simulations; Conformational

9314854 Hermans This study will investigate the equilibria involved in the initiation and growth of alpha-and 310 helices, of turns and of beta strands and the differences in propensity towards formation these structures for different amino acid types. These methods will also be applied to simulation of the activities and inhibition of two enzymes, cytidine deaminase and cyclophilin. The proline isomerase activity of cyclophilin is thought to involve the catalysis of a conformation change, without formation of breaking of a chemical bond. Catalysis by cytidine deaminase appears to require significant conformation change to admit substrate and expel product. Several components of the project will be directed at development or improvement of techniques that may have general applicability. Development of a method (based on work published by Friedman in 1975) to do molecular dynamics simulations of proteins in a spherical "bath" filled with explicit water molecules, with a so-called reaction field that accounts for the presence of a medium with high dielectric constant (water) on the outside, even though no molecules are explicitly represented there. If this implementation is successful, then it will be combined with the fast multipole method (Greengard; Board) for calculation of all long-range electrostatic forces. Other proposed new developments include an improved method for the calculation of absolute binding free energies and the implementation of molecular dynamics programs on parallel machines with many processors. %%% Hardly a single processes involving the action of a protein does not involve a conformation change of some kind, and is fully understood without an understanding of the nature of conformation change. The very process of formation of native protein molecules from an unordered state is a process of coupled and sequential conformation changes that is not at all well understood, and conformation change is critical in the action of nearly all enzymes. This project will apply accurate computer simulation methods to the study of conformation change of peptides and proteins. Molecular dynamics simulations and specialized versions thereof, capable of calculation of free energy differences will be used with a variety of problems. In earlier work the focus of this project has been on validation of the method by application to problems for which precise experimental results are available. This will continue, but increasingly the project will include to problems where experiments have given little or no information about conformational equilibria. %%%

9314854 Hermans 这项研究将研究 α 螺旋、310 螺旋、转角和 β 链的起始和生长所涉及的平衡，以及不同氨基酸类型形成这些结构的倾向差异。 这些方法还将应用于模拟胞苷脱氨酶和亲环蛋白这两种酶的活性和抑制。 亲环蛋白的脯氨酸异构酶活性被认为涉及构象变化的催化，而不形成化学键的断裂。 胞苷脱氨酶的催化似乎需要显着的构象变化以接纳底物并排出产物。 该项目的几个组成部分将致力于开发或改进可能具有普遍适用性的技术。 开发一种方法（基于弗里德曼 1975 年发表的工作），在充满明确水分子的球形“浴”中对蛋白质进行分子动力学模拟，并使用所谓的反应场来解释外部存在高介电常数介质（水），即使那里没有明确表示分子。 如果此实施成功，那么它将与快速多极方法（Greengard；Board）相结合来计算所有远程静电力。 其他提出的新进展包括计算绝对结合自由能的改进方法以及在具有许多处理器的并行机器上实施分子动力学程序。 %%% 几乎没有一个涉及蛋白质作用的过程不涉及某种构象变化，并且在不了解构象变化本质的情况下就可以完全理解。 从无序状态形成天然蛋白质分子的过程是一个耦合且连续的构象变化的过程，这一过程尚不清楚，而构象变化对于几乎所有酶的作用都至关重要。 该项目将应用精确的计算机模拟方法来研究肽和蛋白质的构象变化。 能够计算自由能差异的分子动力学模拟及其专门版本将用于解决各种问题。 在早期工作中，该项目的重点是通过应用于可获得精确实验结果的问题来验证该方法。 这种情况将继续下去，但该项目将越来越多地涉及实验很少或根本没有提供有关构象平衡信息的问题。 %%%