Center for Evolutionary Medicine and Informatics, Biodesign Institute, Arizona State University Tempe, AZ, USA ; Department of Physics, Center for Biological Physics, Bateman Physical Sciences F-Wing, Arizona State University Tempe, AZ, USA.
Evol Appl. 2013 Apr;6(3):423-33. doi: 10.1111/eva.12052. Epub 2013 Feb 13.
Protein structures are dynamic entities with a myriad of atomic fluctuations, side-chain rotations, and collective domain movements. Although the importance of these dynamics to proper functioning of proteins is emerging in the studies of many protein families, there is a lack of broad evidence for the critical role of protein dynamics in shaping the biological functions of a substantial fraction of residues for a large number of proteins in the human proteome. Here, we propose a novel dynamic flexibility index (dfi) to quantify the dynamic properties of individual residues in any protein and use it to assess the importance of protein dynamics in 100 human proteins. Our analyses involving functionally critical positions, disease-associated and putatively neutral population variations, and the rate of interspecific substitutions per residue produce concordant patterns at a proteome scale. They establish that the preservation of dynamic properties of residues in a protein structure is critical for maintaining the protein/biological function. Therefore, structural dynamics needs to become a major component of the analysis of protein function and evolution. Such analyses will be facilitated by the dfi, which will also enable the integrative use of structural dynamics with evolutionary conservation in genomic medicine as well as functional genomics investigations.
蛋白质结构是具有无数原子波动、侧链旋转和整体结构域运动的动态实体。尽管在许多蛋白质家族的研究中，这些动力学对蛋白质正常功能的重要性正在显现，但对于蛋白质动力学在塑造人类蛋白质组中大量蛋白质的大量残基的生物学功能方面的关键作用，缺乏广泛的证据。在这里，我们提出了一种新的动态灵活性指数（dfi）来量化任何蛋白质中单个残基的动态特性，并使用它来评估 100 个人类蛋白质中蛋白质动力学的重要性。我们的分析涉及功能关键位置、与疾病相关和推测为中性的群体变异以及每个残基的种间替换率，在蛋白质组范围内产生了一致的模式。它们表明，在蛋白质结构中保留残基的动态特性对于维持蛋白质/生物学功能至关重要。因此，结构动力学需要成为分析蛋白质功能和进化的主要组成部分。这种分析将通过 dfi 得到促进，这也将使结构动力学与基因组医学以及功能基因组学研究中的进化保守性能够进行综合使用。
