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首页> 外文期刊>Journal of Molecular Biology >Towards a consistent modeling of protein thermodynamic and kinetic cooperativity: how applicable is the transition state picture to folding and unfolding?
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Towards a consistent modeling of protein thermodynamic and kinetic cooperativity: how applicable is the transition state picture to folding and unfolding?

机译：建立蛋白质热力学和动力学协同性的一致模型：过渡状态图在折叠和展开中的适用性如何？

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To what extent do general features of folding/unfolding kinetics of small globular proteins follow from their thermodynamic properties? To address this question, we investigate a new simplified protein chain model that embodies a cooperative interplay between local conformational preferences and hydrophobic burial. The present four-helix-bundle 55mer model exhibits protein-like calorimetric two-state cooperativity. It rationalizes native-state hydrogen exchange observations. Our analysis indicates that a coherent, self-consistent physical account of both the thermodynamic and kinetic properties of the model leads naturally to the concept of a native state ensemble that encompasses considerable conformational fluctuations. Such a multiple-conformation native state is seen to involve conformational states similar to those revealed by native-state hydrogen exchange. Many of these conformational states are predicted to lie below native baselines commonly used in interpreting calorimetric data. Folding and unfolding kinetics are studied under a range of intrachain interaction strengths as in experimental chevron plots. Kinetically determined transition midpoints match well with their thermodynamic counterparts. Kinetic relaxations are found to be essentially single-exponential over an extended range of model interaction strengths. This includes the entire unfolding regime and a significant part of a folding regime with a chevron rollover, as has been observed for real proteins that fold with non-two-state kinetics. The transition state picture of protein folding and unfolding is evaluated by comparing thermodynamic free energy profiles with actual kinetic rates. These analyses suggest that some chevron rollovers may arise from an internal frictional effect that increasingly impedes chain motions with more native conditions, rather than being caused by discrete deadtime folding intermediates or shifts of the transition state peak as previously posited.
机译：小球蛋白的折叠/展开动力学的一般特征在多大程度上从它们的热力学性质出发？为了解决这个问题，我们研究了一种新的简化的蛋白质链模型，该模型体现了局部构象偏好和疏水性埋葬之间的协同相互作用。当前的四螺旋束55mer模型表现出蛋白质样的量热二态协同作用。它使原生态氢交换观测合理化。我们的分析表明，对模型的热力学和动力学特性的连贯，自洽的物理解释自然会导致本机状态集合的概念，该状态包含相当大的构象波动。可以看到这种多构象天然态涉及与天然氢交换所揭示的构象态相似的构象态。预计这些构象状态中的许多处于通常用于解释量热数据的天然基线以下。如实验雪佛龙图所示，在一定范围内的链内相互作用强度下研究折叠和展开动力学。动力学确定的过渡中点与其热力学对应点非常匹配。发现动力学弛豫在模型相互作用强度的扩展范围内基本上是单指数的。这包括带有人字形翻转的整个展开方式和折叠方式的重要部分，正如针对以非两态动力学折叠的真实蛋白质所观察到的那样。通过将热力学自由能谱与实际动力学速率进行比较，可以评估蛋白质折叠和展开的过渡状态图。这些分析表明，某些人字形翻滚可能是由内部摩擦效应引起的，这种内部摩擦效应越来越多地在更多的自然条件下阻碍链运动，而不是由离散的死区折叠中间体或过渡态峰的移位所引起（如先前所述）。

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