Microfolding: Study of Protein Conformation Change by Molecular Dynamics Calculations

赫尔曼斯博士提出分子动力学研究， 研究了构象变化平衡和动力学 肽和蛋白质。 将对系统进行计算 其被几层溶剂明确地溶剂化 分子。 (1)构象自由能表面将是 在4步过程中计算：构象空间将是 通过真空中的动力学模拟探索;概率 将计算每个自由能最小值附近的分布 由自由动力学;自由能之间的差异 构象将由受约束的自由能决定 模拟与施加的扭矩，并通过自由能 分子取代模拟; 将单独探讨最小值。 这些结果将 结合不同的方法使用（自由动力学; 随机模型;过渡态动力学）， 确定障碍物穿越率，即动力学 构象变化的参数。 (2)他计划开发 一种确定氨基酸作用的先验方法， 置换对折叠肽结构的稳定性的影响， 蛋白质的天然折叠构象。 这将具有 其目的是开发技术， 重现可用的实验测得的自由能 变化，并使用有关结构和 热力学动力学模拟是独一无二的 适合提供，从而量化的差异， 潜在的物理效应。 (3)他计划学习 两种酶活性位点的构象柔性 例如：丝氨酸蛋白酶中的侧链柔性，及其 可能与不同底物的特异性有关; 二氢叶酸还原酶抑制剂柔性及其应用 与不同物种酶的特异性有关。 (4)最后，他将尝试区分交替 蛋白质分子的部分构象，即，小的 表面环和肽基团，根据自由能， 为了开发适用于结构的工具， 实验数据不充分时的测定 详细信息。*//

Dr. Hermans proposes molecular dynamics studies to investigate equilibria and kinetics of conformation change of peptides and proteins. Calculations will be done for systems which are explicitly solvated with several layers of solvent molecules. (1) Conformational free energy surfaces will be calculated in a 4-step process: conformation space will be explored by dynamics simulations in vacuo; probability distributions near each free energy minimum will be computed by free dynamics; free energy differences between conformations will be determined by restrained free-energy simulations with applied torques, and by free-energy simulations with molecular substitution; barriers between minima will be explored separately. These results will be used in conjunction with different approaches (free dynamics; a stochastic model; transition state dynamics) in order to determine the rates of barrier crossings, i.e.kinetic parameters of conformation changes. (2) He plans to develop a method for determining a priori the effect of amino acid replacement on the stability of folded peptide structures and of native, folded conformations of proteins. This will have as aims both to develop techniques that consistently reproduce available experimentally measured free energy changes, and to use the details about structure and thermodynamics that the dynamics simulations are uniquely suited to provide, and thereby quantitate the differences in terms of underlying physical effects. (3) He plans to study conformational flexibility in enzyme active sites in two examples: side chain flexibility in serine protease, and its possible relation to specificity for different substrates; inhibitor flexibility in dihydrofolate reductase and its relation to specificity for enzymes from different species. (4) Finally, he will attempt to distinguish alternate conformations of parts of protein molecules, namely, small surface loops and peptide groups, according to free energy, in order to develop a tool applicable in structure determinations where experimental data provide insufficient detail.***//