Center for Soft and Living Matter, Institute for Basic Science, Ulsan 44919, South Korea.
Département de Physique Théorique and Section de Mathématiques, University of Geneva, Geneva, Switzerland.
Mol Biol Evol. 2022 Nov 3;39(11). doi: 10.1093/molbev/msac217.
Proteins need to selectively interact with specific targets among a multitude of similar molecules in the cell. However, despite a firm physical understanding of binding interactions, we lack a general theory of how proteins evolve high specificity. Here, we present such a model that combines chemistry, mechanics, and genetics and explains how their interplay governs the evolution of specific protein-ligand interactions. The model shows that there are many routes to achieving molecular discrimination-by varying degrees of flexibility and shape/chemistry complementarity-but the key ingredient is precision. Harder discrimination tasks require more collective and precise coaction of structure, forces, and movements. Proteins can achieve this through correlated mutations extending far from a binding site, which fine-tune the localized interaction with the ligand. Thus, the solution of more complicated tasks is enabled by increasing the protein size, and proteins become more evolvable and robust when they are larger than the bare minimum required for discrimination. The model makes testable, specific predictions about the role of flexibility and shape mismatch in discrimination, and how evolution can independently tune affinity and specificity. Thus, the proposed theory of specific binding addresses the natural question of "why are proteins so big?". A possible answer is that molecular discrimination is often a hard task best performed by adding more layers to the protein.
蛋白质需要在细胞内众多类似分子中选择性地与特定靶标相互作用。然而，尽管我们对结合相互作用有了坚实的物理理解，但我们缺乏关于蛋白质如何进化出高特异性的一般理论。在这里，我们提出了这样一个模型，它结合了化学、力学和遗传学，并解释了它们的相互作用如何控制特定蛋白质-配体相互作用的进化。该模型表明，有许多途径可以实现分子识别-通过不同程度的灵活性和形状/化学互补性-但关键是精度。更困难的识别任务需要结构、力和运动更集体和精确的协同作用。蛋白质可以通过从结合位点延伸很远的相关突变来实现这一点，从而微调与配体的局部相互作用。因此，通过增加蛋白质的大小，可以实现更复杂任务的解决方案，并且当蛋白质大于识别所需的最小尺寸时，蛋白质变得更具可进化性和鲁棒性。该模型对灵活性和形状不匹配在识别中的作用以及进化如何独立调节亲和力和特异性做出了可测试的、具体的预测。因此，所提出的特异性结合理论解决了“为什么蛋白质这么大？”的自然问题。一个可能的答案是，分子识别通常是一项艰巨的任务，最好通过向蛋白质添加更多层来完成。
