Advances in sequencing techniques and statistical methods have made it possible not only to predict sequences of ancestral proteins but also to identify thousands of mutations in the human exome, some of which are disease associated. These developments have motivated numerous theories and raised many questions regarding the fundamental principles behind protein evolution, which have been traditionally investigated horizontally using the tip of the phylogenetic tree through comparative studies of extant proteins within a family. In this article, we review a vertical comparison of the modern and resurrected ancestral proteins. We focus mainly on the dynamical properties responsible for a protein's ability to adapt new functions in response to environmental changes. Using the Dynamic Flexibility Index and the Dynamic Coupling Index to quantify the relative flexibility and dynamic coupling at a site-specific, single-amino-acid level, we provide evidence that the migration of hinges, which are often functionally critical rigid sites, is a mechanism through which proteins can rapidly evolve. Additionally, we show that disease-associated mutations in proteins often result in flexibility changes even at positions distal from mutational sites, particularly in the modulation of active site dynamics.

中文翻译：

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构象动力学和变构作用在调节蛋白质进化中的作用。

测序技术和统计方法的进步不仅使预测祖先蛋白的序列成为可能，而且还使人们能够识别人类外显子组中的数千种突变，其中一些与疾病有关。这些发展激发了许多理论，并引起了有关蛋白质进化背后基本原理的许多问题，传统上是通过对一个家族中现存蛋白质的比较研究，利用系统发育树的尖端对它们进行水平研究的。在这篇文章中，我们审查了现代和复活的祖传蛋白质的垂直比较。我们主要关注于动态特性，这种动态特性负责蛋白质适应环境变化而适应新功能的能力。使用动态柔韧性指数和动态耦合指数来量化在特定于位点的单氨基酸水平上的相对柔韧性和动态耦合，我们提供了证据，表明铰链的迁移通常是功能关键的刚性位点，蛋白质可以快速进化的机制。此外，我们显示蛋白质中与疾病相关的突变通常会导致柔性变化，即使在突变位点远端的位置，尤其是在活性位点动力学的调节中。