Computational Studies of Peptide Folding Mechanisms

这项拟议的研究试图通过增加对折叠启动的微观相互作用和机制的理解来获得对蛋白质结构的知识。多肽折叠事件将使用构型能量方法、统计力学和统计聚集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。最近对一个在溶液中形成稳定反转的五肽进行了两个极长的分子动力学模拟(每个模拟2.2纳秒)，将通过基于统计的方法进行分析，以确定折叠路径。从模拟获得的大量构象(30,000)将被聚集到结构相似的组中。将分析简化数据集中构象之间的转变以获得协调的二面角变化。导致这些构象转变的机制将从多肽内部和多肽-溶剂相互作用中推断出来，并对每个簇进行评估。这项研究开发了新的技术来分析长时间模拟产生的大量构象，获得的折叠路径知识可以导致设计更计算高效的折叠模拟。聚类分析和对蛋白质结构的其他研究表明，某些N-帽和C-帽构象主导螺旋末端。自由能模拟将被用来确定这些封顶结构对α-螺旋启动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，并考察溶剂结构在封顶中的作用。

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.