Protein—protein binding supersites

The lack of a deep understanding of how proteins interact remains an important roadblock in advancing efforts to identify binding partners and uncover the corresponding regulatory mechanisms of the functions they mediate. Understanding protein-protein interactions is also essential for designing specific chemical modifications to develop new reagents and therapeutics. We explored the hypothesis of whether protein interaction sites serve as generic biding sites for non-cognate protein ligands, just as it has been observed for small-molecule-binding sites in the past. Using extensive computational docking experiments on a test set of 241 protein complexes, we found that indeed there is a strong preference for non-cognate ligands to bind to the cognate binding site of a receptor. This observation appears to be robust to variations in docking programs, types of non-cognate protein probes, sizes of binding patches, relative sizes of binding patches and full-length proteins, and the exploration of obligate and non-obligate complexes. The accuracy of the docking scoring function appears to play a role in defining the correct site. The frequency of interaction of unrelated probes recognizing the binding interface was utilized in a simple prediction algorithm that showed accuracy competitive with other state of the art methods.

对蛋白质相互作用机制缺乏深入认知，仍是阻碍人们鉴定结合伴侣、阐明其介导功能对应调控机制的核心障碍。解析蛋白质-蛋白质相互作用（protein-protein interaction），对于设计特异性化学修饰以开发新型试剂与治疗药物同样至关重要。本研究探讨了如下假说：蛋白质相互作用位点是否可作为非同源蛋白质配体（non-cognate protein ligands）的通用结合位点，正如过往研究中针对小分子结合位点所观测到的现象。我们针对包含241个蛋白质复合物的测试集开展了大规模计算分子对接（computational docking）实验，结果证实非同源配体确实更倾向于结合受体的同源结合位点（cognate binding site）。该观测结果在对接程序类型、非同源蛋白质探针类型、结合斑（binding patch）大小、结合斑与全长蛋白质的相对大小，以及对专性复合物（obligate complex）与非专性复合物（non-obligate complex）的分析中均表现出稳健性。对接打分函数（docking scoring function）的准确性，似乎对正确结合位点的判定具有影响。我们将识别结合界面的无关探针的互作频率应用于一款简易预测算法，该算法的预测准确性可与其他当前最先进的方法相媲美。