Bonet Jaume, Caltabiano Gianluigi, Khan Abdul Kareem, Johnston Michael A, Corbí Carles, Gómez Alex, Rovira Xavier, Teyra Joan, Villà-Freixa Jordi
Computational Biochemistry and Biophysics Laboratory, Research Group on Biomedical Informatics (GRIB), IMIM/UPF, Barcelona, Spain.
Proteins. 2006 Apr 1;63(1):65-77. doi: 10.1002/prot.20791.
Finding why protein-protein interactions (PPIs) are so specific can provide a valuable tool in a variety of fields. Statistical surveys of so-called transient complexes (like those relevant for signal transduction mechanisms) have shown a tendency of polar residues to participate in the interaction region. Following this scheme, residues in the unbound partners have to compete between interacting with water or interacting with other residues of the protein. On the other hand, several works have shown that the notion of active site electrostatic preorganization can be used to interpret the high efficiency in enzyme reactions. This preorganization can be related to the instability of the residues important for catalysis. In some enzymes, in addition, conformational changes upon binding to other proteins lead to an increase in the activity of the enzymatic partner. In this article the linear response approximation version of the semimacroscopic protein dipoles Langevin dipoles (PDLD/S-LRA) model is used to evaluate the stability of several residues in two phosphate hydrolysis enzymes upon complexation with their activating partners. In particular, the residues relevant for PPI and for phosphate hydrolysis in the CDK2/Cyclin A and Ras/GAP complexes are analyzed. We find that the evaluation of the stability of residues in these systems can be used to identify not only active site regions but it can also be used as a guide to locate "hot spots" for PPIs. We also show that conformational changes play a major role in positioning interfacing residues in a proper "energetic" orientation, ready to interact with the residues in the partner protein surface. Thus, we extend the preorganization theory to PPIs, extrapolating the results we obtained from the above-mentioned complexes to a more general case. We conclude that the correlation between stability of a residue in the surface and the likelihood that it participates in the interaction can be a general fact for transient PPIs.
弄清楚蛋白质 - 蛋白质相互作用（PPI）为何如此具有特异性，可为多个领域提供有价值的工具。对所谓瞬时复合物（如与信号转导机制相关的复合物）的统计调查表明，极性残基有参与相互作用区域的倾向。按照此模式，未结合配体中的残基必须在与水相互作用和与蛋白质的其他残基相互作用之间进行竞争。另一方面，多项研究表明，活性位点静电预组织的概念可用于解释酶反应的高效性。这种预组织可能与对催化重要的残基的不稳定性有关。此外，在一些酶中，与其他蛋白质结合时的构象变化会导致酶伴侣的活性增加。在本文中，使用半宏观蛋白质偶极子朗之万偶极子（PDLD/S - LRA）模型的线性响应近似版本来评估两种磷酸水解酶在与它们的激活伴侣复合时几个残基的稳定性。特别地，分析了CDK2/细胞周期蛋白A和Ras/GAP复合物中与PPI以及磷酸水解相关的残基。我们发现，评估这些系统中残基的稳定性不仅可用于识别活性位点区域，还可作为定位PPI“热点”的指南。我们还表明，构象变化在将界面残基定位在合适的“能量”取向上起着主要作用，使其准备好与伴侣蛋白表面的残基相互作用。因此，我们将预组织理论扩展到PPI，将从上述复合物获得的结果外推到更一般的情况。我们得出结论，表面残基的稳定性与其参与相互作用的可能性之间的相关性对于瞬时PPI可能是一个普遍事实。
