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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protein folding by distributed computing and the denatured state ensemble.
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Protein folding by distributed computing and the denatured state ensemble.

机译：通过分布式计算和变性状态集合进行蛋白质折叠。

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The distributed computing (DC) paradigm in conjunction with the folding@home (FH) client server has been used to study the folding kinetics of small peptides and proteins, giving excellent agreement with experimentally measured folding rates, although pathways sampled in these simulations are not always consistent with the folding mechanism. In this study, we use a coarse-grain model of protein L, whose two-state kinetics have been characterized in detail by using long-time equilibrium simulations, to rigorously test a FH protocol using approximately 10,000 short-time, uncoupled folding simulations starting from an extended state of the protein. We show that the FH results give non-Poisson distributions and early folding events that are unphysical, whereas longer folding events experience a correct barrier to folding but are not representative of the equilibrium folding ensemble. Using short-time, uncoupled folding simulations started from an equilibrated denatured state ensemble (DSE), we also do not get agreement with the equilibrium two-state kinetics because of overrepresented folding events arising from higher energy subpopulations in the DSE. The DC approach using uncoupled short trajectories can make contact with traditionally measured experimental rates and folding mechanism when starting from an equilibrated DSE, when the simulation time is long enough to sample the lowest energy states of the unfolded basin and the simulated free-energy surface is correct. However, the DC paradigm, together with faster time-resolved and single-molecule experiments, can also reveal the breakdown in the two-state approximation due to observation of folding events from higher energy subpopulations in the DSE.
机译：分布式计算（DC）范例与folding @ home（FH）客户端服务器结合已用于研究小肽和蛋白质的折叠动力学，与实验测得的折叠速率具有极佳的一致性，尽管在这些模拟中采样的路径并非如此始终与折叠机制一致。在这项研究中，我们使用蛋白质L的粗粒模型，通过使用长时间的平衡模拟详细描述了其两种状态的动力学，使用大约10,000个短时间的非耦合折叠模拟来严格测试FH方案从蛋白质的延伸状态开始。我们显示FH结果给出非物理的非泊松分布和早期折叠事件，而较长的折叠事件遇到正确的折叠障碍，但不代表平衡折叠合奏。使用从平衡的变性状态集合（DSE）开始的短时间，非耦合折叠模拟，由于DSE中较高的能量子群引起的折叠事件过多，因此我们也与平衡态的二态动力学不一致。当从平衡DSE开始时，使用模拟的短轨迹的DC方法可以与传统测得的实验速率和折叠机制联系起来，而模拟时间足够长，可以对未折叠盆地的最低能量状态进行采样，并且模拟的自由能表面为正确。但是，由于观察到DSE中较高能量亚群的折叠事件，DC范式以及更快的时间分辨和单分子实验也可以揭示两种状态的近似分解。

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