水合作用对蛋白质折叠动力学和热力学的重要性:简化晶格模型

Jon M. Sorenson , Teresa Head-Gordon
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引用次数: 27

摘要

背景:最近的研究提出了简化蛋白质折叠模型中协同性起源的各种来源。已讨论的对协同性的重要贡献包括主氢键,侧链填充和疏水相互作用。相关的工作也集中在哪些相互作用是导致天然结构的自由能在自由能景观中成为明显的全球最小值的原因。此外,双味珠模型的折叠协同性较差,往往缺乏独特的天然结构。我们提出了一个简单的多体水化描述,期望它可以改变自由能面,从而增加折叠的协同性,提高双味模型的性能。结果:我们用我们的溶剂化模型和相应的不含溶剂化项的模型研究了设计的36-mer序列在立方晶格上的折叠热力学和动力学。通过列举最紧态来研究自然状态的简并性。采用直方图蒙特卡罗方法得到了折叠温度、状态密度和热容曲线。折叠动力学是通过累积平均首次通过时间与温度的关系来检验的。研究发现,与非溶剂化模型中的序列相比,溶剂化模型中的序列具有更多独特的基态,折叠速度更快,折叠协同性更强。结论:我们发现,加入多体描述溶剂化可以改善双味晶格模型的糟糕性能,并为更多的协同折叠提供了额外的来源。我们的结果表明,更好地描述溶剂化对未来蛋白质折叠的理论研究将是重要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The importance of hydration for the kinetics and thermodynamics of protein folding: simplified lattice models

Background: Recent studies have proposed various sources for the origin of cooperativity in simplified protein folding models. Important contributions to cooperativity that have been discussed include backbone hydrogen bonding, sidechain packing and hydrophobic interactions. Related work has also focused on which interactions are responsible for making the free energy of the native structure a pronounced global minimum in the free energy landscape. In addition, two-flavor bead models have been found to exhibit poor folding cooperativity and often lack unique native structures. We propose a simple multibody description of hydration with expectations that it might modify the free energy surface in such a way as to increase the cooperativity of folding and improve the performance of two-flavor models.

Results: We study the thermodynamics and kinetics of folding for designed 36-mer sequences on a cubic lattice using both our solvation model and the corresponding model without solvation terms. Degeneracies of the native states are studied by enumerating the maximally compact states. The histogram Monte Carlo method is used to obtain folding temperatures, densities of states and heat capacity curves. Folding kinetics are examined by accumulating mean first-passage times versus temperature. Sequences in the proposed solvation model are found to have more unique ground states, fold faster and fold with more cooperativity than sequences in the nonsolvation model.

Conclusions:We find that the addition of a multibody description of solvation can improve the poor performance of two-flavor lattice models and provide an additional source for more cooperative folding. Our results suggest that a better description of solvation will be important for future theoretical protein folding studies.

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