Topology, nucleation, and the protein folding barrier

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性质。因此，它们在确定蛋白质稳定性方面发挥着关键作用，是许多疾病状态的潜在原因，并且是技术挑战和创新的潜在来源。尽管这些重要问题引发了数十年的仔细研究，然而，还没有定量的、实验验证的假设来解释蛋白质折叠是如何比随机构象搜索快30多个数量级的。提出的研究计划的目标是通过成功结合一种新颖的、完全原子的、大规模并行的方法来模拟蛋白质折叠，并在直接可比的条件下对相关蛋白质进行实验表征，从而进一步了解折叠过程。我们的动机很简单。简单蛋白质折叠的实验研究最多只能提供折叠过渡态的有限视图。相比之下，模拟可以提供任意详细的折叠表示（仅受精度和计算复杂性耦合问题的限制）。然而，它们严重依赖于实验验证，缺乏一种明确的、普遍认可的方法来识别过渡态系综的成员。通过仿真与实验相结合，可以克服这些困难；这种结合提供了一种“充实”实验中隐藏的细节的方法，提供了一种无懈可击的验证模拟的方法，并为识别限速跃迁提供了指导。受到这些潜在优势的启发，我们在这里提出了一种新颖的，在迭代过程中模拟和实验的密切耦合，从而显着提高了两者的效用。连接模拟和实验的历史困难在于，小的、快速折叠的蛋白质很难通过实验来检验，而大的和/或缓慢折叠的蛋白质很难通过详细的模拟来检验。然而，正如重要的初步结果所表明的那样，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，直接比较详细的模拟结果与实验观察。

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.