Hot regions in protein-protein interactions: The organization and contribution of structurally conserved hot spot residues
Hot regions in protein-protein interactions: The organization and contribution of structurally conserved hot spot residues
复制标题
DOI：
10.1016/j.jmb.2004.10.077
复制
发表时间：
2005-02-04
影响因子：
5.6
通讯作者：
Nussinov, R
中科院分区：
文献类型：
--
作者：
Keskin, O;Ma, BY;Nussinov, R
蛋白质-蛋白质界面上结构保守的残基与实验丙氨酸扫描热点相关。在这里，我们研究了这些保守的计算热点的组织及其对蛋白质结合稳定性的贡献。我们发现计算热点沿蛋白质界面分布不均匀；相反，它们聚集在局部紧密排列的区域内。在密集的集群中，它们形成了一个相互作用的网络，因此它们对复合物稳定性的贡献是合作的；然而，独立簇的贡献是加性的。这表明束缚自由能不是单个热点残馀贡献的简单总和。正如预期的那样，在热点残基周围，我们观察到适度保守的残基，进一步强调了保守相互作用在局部密集环境中的关键作用。这些组织的保守发生表明它们有利于蛋白质-蛋白质结合。有趣的是，热点贡献的氢键和盐桥的总数与预期一致。因此，氢键形成残基可能使用“热点排除水”机制。由于保守残基位于高度填充的区域，水分子在结合时很容易被移除，从而加强了电荷-电荷相互作用的静电贡献。因此，出现的图像是蛋白质-蛋白质结合是局部优化的，聚集的，网络化的，高度包装的结构保守残基对复合物的稳定性起着主导作用和协同作用。在解决“蛋白质结合的首选方式是什么”这一关键问题时，这些发现指出了热区在蛋白质-蛋白质相互作用中的关键作用。(C) 2004 Elsevier Ltd.版权所有。
Structurally conserved residues at protein-protein interfaces correlate with the experimental alanine-scanning hot spots. Here, we investigate the organization of these conserved, computational hot spots and their contribution to the stability of protein associations. We find that computational hot spots are not homogeneously distributed along the protein interfaces; rather they are clustered within locally tightly packed regions. Within the dense clusters, they form a network of interactions and consequently their contributions to the stability of the complex are cooperative; however the contributions of independent clusters are additive. This suggests that the binding free energy is not a simple summation of the single hot spot residue contributions. As expected, around the hot spot residues we observe moderately conserved residues, further highlighting the crucial role of the conserved interactions in the local densely packed environment. The conserved occurrence of these organizations suggests that they are advantageous for protein-protein associations. Interestingly, the total number of hydrogen bonds and salt bridges contributed by hot spots is as expected. Thus, H-bond forming residues may use a "hot spot for water exclusion" mechanism. Since conserved residues are located within highly packed regions, water molecules are easily removed upon binding, strengthening electrostatic contributions of charge-charge interactions.Hence, the picture that emerges is that protein-protein associations are optimized locally, with the clustered, networked, highly packed structurally conserved residues contributing dominantly and cooperatively to the stability of the complex. When addressing the crucial question of "what are the preferred ways of proteins to associate", these findings point toward a critical involvement of hot regions in protein-protein interactions. (C) 2004 Elsevier Ltd. All rights reserved.