[论文解读] A Structure-Centric View of Protein Evolution, Design and Adaptation

Eric J. Deeds, Eugene I. Shakhnovich|ArXiv.org|Mar 22, 2006

Protein Structure and Dynamics参考文献 109被引用 13

一句话总结

本文提出了一种以结构为中心的框架，用于理解蛋白质进化，强调蛋白质序列如何演化以形成稳定的三维折叠。该框架整合了理论模型与经验数据，解释了蛋白质折叠分布的不均衡性，揭示了结构创新通过序列分歧产生，且某些拓扑结构因稳定性和进化可及性而更受青睐。

ABSTRACT

Proteins, by virtue of their central role in most biological processes, represent one of the key subjects of the study of molecular evolution. Inherent to the indispensability of proteins for living cells is the fact that a given protein can adopt a specific three-dimensional shape that is specified solely by the proteins sequence of amino acids. Over the past several decades, structural biologists have demonstrated that the array of structures that proteins may adopt is quite astounding, and this has lead to a strong interest in understanding how protein structures change and evolve over time. In this review we consider a large body of recent work that attempts to illuminate this structure-centric picture of protein evolution. Much of this work has focused on the question of how completely new protein structures (i.e. new folds or topologies) are discovered by protein sequences as they evolve. Pursuant to this question of structural innovation has been a desire to describe and understand the observation that certain types of protein structures are far more abundant than others and how this uneven distribution of proteins implicates on the process through which new shapes are discovered. We consider a number of theoretical models that have been successful at explaining this heterogeneity in protein populations and discuss the increasing amount of evidence that indicates that the process of structural evolution involves the divergence of protein sequences and structures from one another.

研究动机与目标

• 理解新蛋白质折叠在进化过程中出现的机制。
• 解释基因组中蛋白质结构分布不均的成因。
• 研究序列进化如何导致结构分歧并催生新型拓扑结构。
• 评估结构稳定性和可折叠性在塑造蛋白质进化轨迹中的作用。
• 将理论模型与生物数据整合，描述蛋白质架构的进化动态。

提出的方法

• 应用统计力学与能量景观理论，模拟蛋白质折叠与稳定性。
• 利用计算模拟探索序列到结构的映射关系及进化路径。
• 分析经验蛋白质结构数据库，量化折叠的丰度与分布。
• 开发理论模型，基于拓扑复杂性与稳定性预测结构创新的可能性。
• 将进化分歧模型与结构约束相结合，模拟长期的结构进化。
• 将预测的折叠分布与实际基因组数据对比，以验证模型。

实验结果

研究问题

• RQ1 为何在基因组中某些蛋白质折叠显著比其他折叠更丰富？
• RQ2 支撑新型蛋白质拓扑结构出现的进化机制是什么？
• RQ3 蛋白质结构的稳定性在多大程度上影响其进化可及性？
• RQ4 序列变化在多大程度上导致蛋白质进化中的结构分歧？
• RQ5 是什么决定了对特定结构基序的进化偏好，而非其他基序？

主要发现

• 蛋白质折叠表现出高度非均匀的分布，少数拓扑结构主导了整个基因组。
• 结构稳定性和崎岖的能量景观有利于某些折叠在进化中脱颖而出。
• 理论模型预测，结构创新通过在折叠稳定性引导下的序列空间探索而发生。
• 结构稳定性更高的折叠在进化过程中更可能被发现并保留。
• 序列分歧通常导致结构分歧，支持了新折叠通过渐进式进化变化产生的观点。
• 某些折叠的丰度与它们的拓扑简单性及易折叠性相关，表明存在进化可及性的偏向。