蛋白质-蛋白质相互作用的结构发生过程，这一成果由斯坦福大学医学院
研究团队以合成协同进化为主题来设计naVe表面，模拟蛋白质复合体的从头形成。研究小组分离出7个不同结构家族的蛋白质z结构域复合物，发现合成复合物通过棘轮状对接模式探索多个浅层能量井，而由天然结合位点形成的复合物则以相对固定的几何形状聚集在深能量井中。对机器学习估计的适应度景观的上位分析揭示了结合伙伴之间的“种子”接触，这些接触锚定了相遇复杂形成的最早阶段。他们的研究结果表明，与自然结合位点相比，“沉默”的表面具有较浅的能量景观，不利于紧密结合，可能是由于进化的反选择。
据悉，了解蛋白质结合位点如何演变与其他蛋白质的相互作用，可以为靶向“不可药物”表面提供线索。
附：英文原文
Title: Structural ontogeny of protein-protein interactions
Author: Aerin Yang, Hanlun Jiang, Kevin M. Jude, Deniz Akpinaroglu, Stephan Allenspach, Alex Jie Li, James Bowden, Carla Patricia Perez, Liu Liu, Po-Ssu Huang, Tanja Kortemme, Jennifer Listgarten, K. Christopher Garcia
Issue&Volume: 2026-02-12
Abstract: Understanding how protein binding sites evolve interactions with other proteins could hold clues to targeting “undruggable” surfaces. We used synthetic coevolution to engineer new interactions between nave surfaces, simulating the de novo formation of protein complexes. We isolated seven distinct structural families of protein Z-domain complexes and found that synthetic complexes explore multiple shallow energy wells through ratchet-like docking modes, whereas complexes formed by natural binding sites converged in a deep energy well with a relatively fixed geometry. Epistasis analysis of a machine learning–estimated fitness landscape revealed “seed” contacts between binding partners that anchored the earliest stages of encounter complex formation. Our results suggest that “silent” surfaces have a shallower energy landscape than natural binding sites, disfavoring tight binding, likely owing to evolutionary counterselection.
DOI: adx6931
Source: https://www.science.org/doi/10.1126/science.adx6931