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

9314854赫曼斯本研究将调查α-和310型螺旋、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的差异。这些方法还将用于模拟胞苷脱氨酶和亲环素两种酶的活性和抑制作用。亲环素的脯氨酸异构酶活性被认为涉及构象变化的催化，而不是形成化学键的断裂。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用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)，在充满显式水分子的球形“浴缸”中对蛋白质进行分子动力学模拟，所谓的反应场解释了外部存在具有高介电常数(水)的介质，即使那里没有显式表示的分子。如果实施成功，那么它将与快速多极子方法(Greengard；Board)相结合，用于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和在具有多个处理器的并行机上执行分子动力学程序。几乎没有一个涉及蛋白质作用的单一过程不涉及某种构象变化，并且在不理解构象变化的性质的情况下被完全理解。天然蛋白质分子从无序状态形成的过程是一个耦合的、连续的构象变化过程，这一过程还没有被很好地理解，而构象变化在几乎所有酶的作用中都是至关重要的。该项目将应用精确的计算机模拟方法来研究多肽和蛋白质的构象变化。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，这个项目的重点一直是通过应用于有精确实验结果的问题来验证该方法。这将继续下去，但该项目将越来越多地包括那些实验很少或根本没有给出关于构象平衡的信息的问题。%%%

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. %%%