Computational Studies of Peptide Folding Mechanisms

这项拟议中的研究旨在获得蛋白质的知识 通过增加对微观结构的理解， 折叠起始的相互作用和机制。 肽 折叠事件将研究使用一种新的组合， 构型能量方法，统计力学， 统计聚类技术。 导致新生折叠事件的微观机制 一般是未知的。 两个超长分子动力学 模拟（每个2.2纳秒），最近在一个 五肽在溶液中形成稳定的逆转， 通过基于统计的方法进行分析，以识别折叠 途径。 大量的构象获得从 模拟（30，000）将被聚类到结构相似的 组 还原态的构象之间的转变 将分析数据集的一致二面角变化。 引起这些构象转变的机制将是 从肽内和肽-溶剂相互作用推断， 对每个集群进行评估。 这项研究开发了新的技术 用于分析大量的构象， 长时间的模拟，以及获得的折叠途径的知识 可以设计出计算效率更高的折叠 模拟 蛋白质结构的聚类分析和其他研究 已经表明，某些N-帽和C-帽构象占主导地位， 螺旋末端 自由能模拟将用于确定 自由能的贡献，这些盖帽结构的a- 螺旋起始和增殖，以及它们作为 螺旋停止信号。 自由能贡献给螺旋 将计算电荷/螺旋偶极相互作用的形成， 将考察溶剂结构在封端中的作用。

The proposed research seeks to gain knowledge of protein structure through increased understanding of the microscopic interactions and mechanisms of folding initiation. Peptide folding events will be studied using a novel combination of configurational energy methods, statistical mechanics and statistical clustering techniques. The microscopic mechanisms leading to nascent folding events are generally unknown. Two extremely long molecular dynamics simulations (2.2 nanoseconds each), recently carried out on a pentapeptide that forms stable reverse turns in solutions, will be analyzed by statistically based methods to identify folding pathways. The large number of conformations obtained from the simulations (30,000) will be clustered into structurally similar groups. Transitions between the conformations in the reduced data set will be analyzed for concerted dihedral angle changes. The mechanisms causing these conformational transitions will be deduced from intra-peptide and peptide-solvent interactions, assessed for each cluster. This research develops new techniques for the analysis of large numbers of conformations resulting from long simulations, and the knowledge of folding pathways gained can lead to the design of more computationally efficient folding simulations. Cluster analysis and other surveys of protein structures have shown that certain N-cap and C-cap conformations dominate helix termini. Free energy simulations will be used to determine the free energy contribution of these capping structures to a- helix initiation and propagation, and their potential to act as helix stop signals. The free energy contributed to helix formation by charge/helix dipole interactions will be calculated, an the role of solvent structure in capping will be examined.