Formation mechanisms of native states of small proteins

描述（由申请人提供）：蛋白质折叠和错误折叠机制的全面阐明需要详细了解导致天然和非天然状态形成的分子事件。最近的进展，这位研究人员帮助开发，已经有可能研究微秒时间尺度的分子事件，导致形成一个天然的小蛋白质与蛋白质和溶剂的全原子表示状态。我们将应用全原子分子动力学模拟与显式和连续溶剂模型来表征与小蛋白质和肽的折叠和错误折叠相关的非天然状态。这项建议将逐步解决三个关键领域。两个拓扑结构简单的蛋白质，包括FSD 1（β/β/α模块）和蛋白质A（三螺旋束）的模拟，将使我们能够研究三级结构的形成及其对二级结构的依赖性。对疏水相互作用的作用的见解也有望出现。三级和二级结构的形成将进一步检查两个拓扑结构的挑战性蛋白质，包括蛋白G（α/β蛋白）和单体λ阻遏物（α-螺旋蛋白）的模拟。在这两种蛋白质的折叠过程中可以形成多个疏水簇。因此，观察它们如何结合以及如何重新包装是很有趣的。我们将开发精确的蛋白质折叠模拟和蛋白质结构预测的方法。我们将着重于起始，疏水核心，三级结构的形成和它对二级结构的依赖。与实验的比较，包括对我们模型的预测能力的直接测试，将是我们研究的一个组成部分，并将有助于对方法进行仔细审查。

DESCRIPTION (provided by applicant): Full elucidation of the mechanisms of protein folding and misfolding requires detailed knowledge of the molecular events leading to the formation of both native and non-native states. Recent advances, which this investigator has helped to develop, have made it possible to study microsecond time-scale molecular events leading to the formation of a native-like state of a small protein with an all-atom representation of both protein and solvent. We will apply all-atom molecular dynamics simulations with both explicit and continuum solvent models to characterize the non-native states that are relevant to the folding and misfolding of small proteins and peptides. This proposal will incrementally address three key areas. Simulations on two topologically simple proteins, including FSD1 (a beta/beta/alpha module) and protein A (a three-helix bundle), will allow us to study tertiary structure formation and its dependence on the secondary structures. Insights on the role of hydrophobic interactions are also expected to emerge. Tertiary and secondary structure formation will be examined further by simulations of two topologically challenging proteins, including protein G (an alpha/beta protein) and monomeric lambda repressor (an alpha-helical protein). Multiple hydrophobic clusters may form during folding of these two proteins. It is therefore interesting to see how they coalesce and how they repack. We will develop methods for accurate protein folding simulation and protein structure prediction. We will focus on initiation, hydrophobic core, tertiary structure formation and its dependence on the secondary structures. Comparison with experiments, including direct tests on the predictive ability of our model will be an integral part of our study and will be instrumental for a close scrutiny on the approach.