Interactions between proteins are vital in almost all biological processes. The characterization of protein–protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for biotechnological and clinical purposes. The interface residues of a protein–protein complex are assumed to have the following two properties: (a) they always interact with a residue of a partner protein, which forms the basis for distance-based interface residue identification methods, and (b) they are solvent-exposed in the isolated form of the protein and become buried in the complex form, which forms the basis for Accessible Surface Area (ASA)-based methods. The study interrogates this popular assumption by recognizing interface residues in protein–protein complexes through these two methods. The results show that a few residues are identified uniquely by each method, and the extent of conservation, propensities, and their contribution to the stability of protein–protein interaction varies substantially between these residues. The case study analyses showed that interface residues, unique to distance, participate in crucial interactions that hold the proteins together, whereas the interface residues unique to the ASA method have a potential role in the recognition, dynamics, and specificity of the complex and can also be a hotspot. Overall, the study recommends applying both distance and ASA methods so that some interface residues missed by either method but crucial to the stability, recognition, dynamics, and function of protein–protein complexes are identified in a complementary manner.

中文翻译：

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蛋白质-蛋白质复合物中的界面残留物是仁者见仁智者见智的

蛋白质之间的相互作用在几乎所有生物过程中都至关重要。蛋白质-蛋白质相互作用的表征有助于我们了解生物过程的机制基础，从而能够出于生物技术和临床目的操纵蛋白质。假设蛋白质-蛋白质复合物的界面残基具有以下两个特性：（a）它们总是与伴侣蛋白质的残基相互作用，这构成了基于距离的界面残基识别方法的基础，以及（b）它们以蛋白质的分离形式暴露于溶剂中，并以复杂形式埋藏，这构成了基于可及表面积（ASA）的方法的基础。该研究通过这两种方法识别蛋白质-蛋白质复合物中的界面残基，质疑了这一流行的假设。结果表明，每种方法都独特地鉴定了一些残基，并且这些残基之间的保守程度、倾向及其对蛋白质-蛋白质相互作用稳定性的贡献有很大差异。案例研究分析表明，距离特有的界面残基参与将蛋白质结合在一起的关键相互作用，而 ASA 方法特有的界面残基在复合物的识别、动力学和特异性方面具有潜在作用，并且还可以成为热点。总体而言，该研究建议同时应用距离和 ASA 方法，以便以互补的方式鉴定一些被任一方法遗漏但对蛋白质-蛋白质复合物的稳定性、识别、动力学和功能至关重要的界面残基。