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

9314854 Hermans本研究将研究α-和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。 这些方法也将被应用于模拟两种酶，胞苷脱氨酶和亲环素的活性和抑制。 亲环素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。 胞苷脱氨酶的催化作用似乎需要显著的构象变化来接纳底物和排出产物。 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。 开发了一种方法（基于Friedman在1975年发表的工作），在充满明确水分子的球形“浴”中进行蛋白质的分子动力学模拟，具有所谓的反应场，该反应场解释了外部具有高介电常数的介质（水）的存在，即使没有分子明确表示。 如果这种实施是成功的，那么它将与快速多极方法（格林加德;董事会）计算所有的远程静电力。 其他提出的新的发展包括一个改进的方法计算的绝对结合自由能和分子动力学程序的并行机与许多处理器的实施。 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，并且在不理解构象变化的本质的情况下被完全理解。 从无序状态形成天然蛋白质分子的过程是一个偶联和连续构象变化的过程，这一过程根本没有得到很好的理解，而构象变化在几乎所有酶的作用中都是至关重要的。 本计画将应用精确的电脑模拟方法，研究多肽与蛋白质的构象变化。 分子动力学模拟及其专门版本，能够计算自由能差将用于各种问题。 在早期的工作中，该项目的重点一直是验证的方法，通过应用程序的问题，精确的实验结果是可用的。 这将继续下去，但越来越多的项目将包括问题的实验给出很少或根本没有信息的构象平衡。 %%%

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. %%%