Topology, nucleation, and the protein folding barrier

拓扑、成核和蛋白质折叠屏障

• 批准号: 6757836
• 负责人: VIJAY S PANDE
• 金额: $ 23.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757836
• 关键词: chemical stability; computer simulation; conformation; mathematical model; protein biosynthesis; protein folding; protein reconstitution

DESCRIPTION (provided by applicant): Protein folding, unfolding and misfolding are fundamental physical properties of biomaterials. As such, they play critical roles in defining protein stability, are the underlying cause of many disease states and serve as a potential source of both technological challenges and innovations. Despite the decades of scrutiny motivated by these important issues, however, no quantitative, experimentally verified hypothesis yet explains how protein folding occurs some 30+ orders of magnitude more rapidly than would a random conformational search. The goal of the proposed research program is to further our understanding of the folding process via the successful marriage of a novel, fully atomistic, massively parallel method for simulating protein folding with the experimental characterization of the relevant proteins under directly comparable conditions. Our motivation is straightforward. Experimental studies of the folding of simple proteins provide at best only a limited view of the folding transition-state. Simulations, in contrast, can provide an arbitrarily detailed representation of folding (limited only by the coupled issues of accuracy and computational complexity). They are, however, critically dependent on experimental validation and lack a clear, universally recognized means of identifying members of the transition state ensemble. By coupling simulation with experiment, we can circumvent these difficulties; the combination furnishes a method of "fleshing-out" the details otherwise hidden to experiment, provides an unimpeachable means of validating the simulations and offers guidance in the identification of the rate limiting transition. Inspired by these potential advantages, we propose here a novel, intimate coupling of simulation and experiment in an iterative process that significantly increases the utility of both.The historical difficulty with connecting simulation and experiment has been the conflict that small, rapidly folding proteins are difficult to examine experimentally, whereas large and/or slowly folding proteins are difficult to examine via detailed simulations. As significant preliminary results demonstrate, however, recent advances in both simulation and experiment now allow us to resolve this conflict. We have exploited these advances to reach and test multi-use, fully detailed folding simulations, providing a unique opportunity to directly compare the outcome of detailed simulations with experimental observations.

描述（由申请人提供）：蛋白质折叠，展开和错误折叠是生物材料的基本物理特性。因此，它们在定义蛋白质稳定性方面起着至关重要的作用，是许多疾病状态的根本原因，并且是技术挑战和创新的潜在来源。尽管有这些重要问题的审查数十年，但是没有定量，实验验证的假设，但解释了蛋白质折叠的发生率是如何比随机构象搜索更快的30多个数量级。 拟议的研究计划的目的是通过成功的结婚，通过在直接可比条件下的相关蛋白质的实验表征对蛋白质折叠进行模拟蛋白质折叠的成功结婚，以进一步了解折叠过程。我们的动力很简单。简单蛋白质折叠的实验研究充其量只能提供折叠过渡状态的有限视图。相比之下，模拟可以提供折叠的任意详细表示（仅受精度和计算复杂性的耦合问题的限制）。但是，它们非常依赖于实验验证，并且缺乏清晰，普遍认可的识别过渡状态合奏成员的手段。通过将模拟与实验耦合，我们可以规避这些困难。该组合提供了一种“散开”实验中隐藏的细节的方法，它提供了一种无法实现的方法来验证模拟并在识别速率限制过渡时提供指导。受这些潜在优势的启发，我们在这里提出了一个新颖的模拟和实验过程中的亲密耦合，从而大大增加了两者的效用。连接模拟和实验的历史困难是很难进行实验性检验的小，快速折叠的蛋白质，而较大的大型和/或缓慢折叠的蛋白质则难以通过sime sim simaulcation进行。然而，由于重要的初步结果表明，模拟和实验的最新进展现在使我们能够解决这一冲突。我们已经利用了这些进步来达到和测试多用途，完全详细的折叠模拟，提供了一个独特的机会，可以将详细模拟的结果与实验观察直接进行比较。