Protein folding funnels: The nature of the transition state ensemble
Protein folding funnels: The nature of the transition state ensemble
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DOI：
10.1016/s1359-0278(96)00060-0
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发表时间：
1996-01-01
期刊：
影响因子：
--
通讯作者：
Wolynes, PG
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文献类型：
--
作者：
Onuchic, JN;Socci, ND;Wolynes, PG
背景：能量景观理论预测一个小的快速折叠α -螺旋蛋白的折叠漏斗将有一个过渡状态到自然状态的一半。根据观察到的折叠和展开速率常数作为变性剂浓度函数的线性自由能关系，可以沿适当的反应坐标估计过渡态的位置。Huang和Gas研究lambda阻遏因子，Fersht和合作者研究Cl2， Gray和合作者研究细胞色素c的实验结果表明，在折叠区和未折叠区之间存在自由能障。这个障碍来自于折叠过程中的熵瓶颈。结果：与实验结果一致，基于折叠漏斗描述的晶格模拟表明，过渡态不仅仅是一个单一的构象，而是一个相对大量的构象的集合，这些构象可以通过一个或几个顺序参数的特定值（例如原生接触的分数）来描述。从我们的晶格模拟和Boczko和Brooks的小螺旋蛋白的原子模型中对过渡态或瓶颈区进行的分析表明，在过渡态系综中，原生接触参与的分布广泛，中心约为50%。然而，重要的是，晶格模拟的过渡态系综确实包括一些特别热的接触，正如在实验中看到的那样，这些接触被其他人称为折叠核。结论：线性自由能关系提供了过渡态的粗略光谱，使我们能够根据天然接触的分数推断反应坐标的值。这个瓶颈可以被认为是一个离域核的集合，其中不同的本地接触将具有不同程度的参与。实验结果与理论预测一致，为景观分析提供了有力的支持。(C)现代生物有限公司
Background: Energy landscape theory predicts that the folding funnel for a small fast-folding alpha-helical protein will have a transition state half-way to the native state. Estimates of the position of the transition state along an appropriate reaction coordinate can be obtained from linear free energy relationships observed for folding and unfolding rate constants as a function of denaturant concentration. The experimental results of Huang and Gas for lambda repressor, Fersht and collaborators for Cl2, and Gray and collaborators for cytochrome c indicate a free energy barrier midway between the folded and unfolded regions. This barrier arises from an entropic bottleneck for the folding process.Results: In keeping with the experimental results, lattice simulations based on the folding funnel description show that the transition state is not just a single conformation, but rather an ensemble of a relatively large number of configurations that can be described by specific values of one or a few order parameters (e.g. the fraction of native contacts). Analysis of this transition state or bottleneck region from our lattice simulations and from atomistic models for small oc-helical proteins by Boczko and Brooks indicates a broad distribution for native contact participation in the transition state ensemble centered around 50%. Importantly, however, the lattice-simulated transition state ensemble does include some particularly hot contacts, as seen in the experiments, which have been termed by others a folding nucleus.Conclusions: Linear free energy relations provide a crude spectroscopy of the transition state, allowing us to infer the values of a reaction coordinate based on the fraction of native contacts. This bottleneck may be thought of as a collection of delocalized nuclei where different native contacts will have different degrees of participation. The agreement between the experimental results and the theoretical predictions provides strong support for the landscape analysis. (C) Current Biology Ltd.