National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2010 Jan 6;5(1):e8591. doi: 10.1371/journal.pone.0008591.
Understanding the residue covariations between multiple positions in protein families is very crucial and can be helpful for designing protein engineering experiments. These simultaneous changes or residue coevolution allow protein to maintain its overall structural-functional integrity while enabling it to acquire specific functional modifications. Despite the significant efforts in the field there is still controversy in terms of the preferable locations of coevolved residues on different regions of protein molecules, the strength of coevolutionary signal and role of coevolution in functional diversification.
In this paper we study the scale and nature of residue coevolution in maintaining the overall functionality and structural integrity of proteins. We employed a large scale study to investigate the structural and functional aspects of coevolved residues. We found that the networks representing the coevolutionary residue connections within our dataset are in general of 'small-world' type as they have clustering coefficient values higher than random networks and also show smaller mean shortest path lengths similar and/or lower than random and regular networks. We also found that altogether 11% of functionally important sites are coevolved with any other sites. Active sites are found more frequently to coevolve with any other sites (15%) compared to protein (11%) and ligand (9%) binding sites. Metal binding and active sites are also found to be more frequently coevolved with other metal binding and active sites, respectively. Analysis of the coupling between coevolutionary processes and the spatial distribution of coevolved sites reveals that a high fraction of coevolved sites are located close to each other. Moreover, approximately 80% of charge compensatory substitutions within coevolved sites are found at very close spatial proximity (<or= 5A), pointing to the possible preservation of salt bridges in evolution.
Our findings show that a noticeable fraction of functionally important sites undergo coevolution and also point towards compensatory substitutions as a probable coevolutionary mechanism within spatially proximal coevolved functional sites.
理解蛋白质家族中多个位置之间的残基协变非常关键，有助于设计蛋白质工程实验。这些同时发生的变化或残基共进化允许蛋白质在保持整体结构-功能完整性的同时，获得特定的功能修饰。尽管在该领域做出了重大努力，但在共进化残基在蛋白质分子不同区域的优选位置、共进化信号的强度以及共进化在功能多样化中的作用方面仍存在争议。
在本文中，我们研究了残基共进化在维持蛋白质整体功能和结构完整性方面的规模和性质。我们进行了大规模研究，以调查共进化残基的结构和功能方面。我们发现，代表我们数据集内共进化残基连接的网络通常具有“小世界”类型，因为它们的聚类系数值高于随机网络，并且还显示出较小的平均最短路径长度，类似于/或低于随机和规则网络。我们还发现，总共 11%的功能重要位点与其他任何位点共进化。与蛋白质（11%）和配体（9%）结合位点相比，活性位点更频繁地与任何其他位点共进化（15%）。金属结合和活性位点也分别发现与其他金属结合和活性位点更频繁地共进化。共进化过程与共进化位点空间分布之间的耦合分析表明，很大一部分共进化位点彼此靠近。此外，在共进化位点内约 80%的电荷补偿性取代发生在非常接近的空间位置（<或=5A），表明盐桥在进化中可能得到了保存。
我们的发现表明，相当一部分功能重要的位点经历了共进化，并且指出补偿性取代可能是空间上接近的共进化功能位点内的共进化机制。
