Computational Studies of Peptide Folding Mechanisms

拟议的研究旨在通过增加对微观相互作用和折叠起始机制的理解来获得蛋白质结构的知识。肽折叠事件将使用构型能量方法、统计力学和统计聚类技术的新组合来研究。导致新生折叠事件的微观机制通常是未知的。最近在溶液中形成稳定反转的五肽上进行了两次极长分子动力学模拟（每次2.2纳秒），将通过基于统计的方法来分析折叠途径。从模拟中获得的大量构象（30,000）将聚集成结构相似的组。简化数据集中的构象之间的转换将被分析为协调的二面角变化。引起这些构象转变的机制将从肽内和肽-溶剂相互作用中推断出来，并对每个簇进行评估。本研究为长时间模拟产生的大量构象的分析开发了新技术，并且获得的折叠路径知识可以导致设计更具计算效率的折叠模拟。对蛋白质结构的聚类分析和其他调查表明，某些N-cap和C-cap构象支配着螺旋末端。自由能模拟将用于确定这些封盖结构对a-螺旋起始和传播的自由能贡献，以及它们作为螺旋停止信号的潜力。将计算电荷/螺旋偶极相互作用对螺旋形成的自由能，并研究溶剂结构在旋盖中的作用。

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.