蛋白质折叠和结合可以通过结构偶联作为进化的拱肩出现
Protein folding and binding can emerge as evolutionary spandrels through structural coupling
摘要：
蛋白质和其他分子之间的结合相互作用介导许多细胞过程，包括代谢、信号传导和基因表达的调节。这些相互作用的进化是为了响应蛋白质的化学或物理环境的变化（如添加抗生素），或者当基因复制和分化时。最近的几项研究表明，折叠稳定性在限制蛋白质进化中的重要性。在这里，我们调查如何结构之间的耦合蛋白质折叠和结合-事实上，大多数蛋白质只能结合其目标时折叠-引起的进化之间的耦合特性的折叠稳定性和结合强度。使用生物物理和进化建模，我们展示了这些蛋白质性状如何成为进化的“拱肩”，即使它们不赋予内在的健身优势。特别是，蛋白质可以进化出强的结合相互作用，其没有功能作用，而仅仅在错误折叠有害的情况下起到稳定蛋白质的作用。此外，这些蛋白质可能具有不同的命运，根据随机突变事件进化为结合或不结合其靶标。这些观察结果可以解释在高通量测定中观察到的蛋白质之间的明显非功能性相互作用的丰度。相反，对于具有功能性结合和有害错误折叠的蛋白质，进化在生物物理特征的水平上可能是高度可预测的：适应性路径被严格限制为首先获得额外的折叠稳定性，然后随着新的结合功能的发展而部分失去它。这些发现对于我们理解天然和工程蛋白质的基本进化原理具有重要意义。
英文摘要：
Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and regulation of gene expression. These interactions evolve in response to changes in the protein's chemical or physical environment (such as the addition of an antibiotic), or when genes duplicate and diverge. Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between protein folding and binding -- the fact that most proteins can only bind their targets when folded -- gives rise to evolutionary coupling between the traits of folding stability and binding strength. Using biophysical and evolutionary modeling, we show how these protein traits can emerge as evolutionary "spandrels" even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if misfolding is deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutation events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of fundamental evolutionary principles of both natural and engineered proteins.
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