Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
J Mol Biol. 2012 Jan 13;415(2):419-28. doi: 10.1016/j.jmb.2011.11.009. Epub 2011 Nov 12.
Understanding the structural basis of protein-protein interactions (PPIs) may shed light on the organization and functioning of signal transduction and metabolic networks and may assist in structure-based design of ligands (drugs) targeting protein-protein interfaces. The residues at the bimolecular interface, designated as the hot spots, contribute most of the free binding energy of PPI. To date, there is no conclusive atomistic explanation for the unique functional properties of the hot spots. We hypothesized that backbone compliance may play a role in protein-protein recognition and in the mechanism of binding of small-molecule compounds to protein surfaces. We used a steered molecular dynamics simulation to explore the compliance properties of the backbone of surface-exposed residues in several model proteins: interleukin-2, mouse double minute protein 2 and proliferating cell nuclear antigen. We demonstrated that protein surfaces exhibit distinct patterns in which highly immobile residues form defined clusters ("stability patches") alternating with areas of moderate to high mobility. These "stability patches" tend to localize in functionally important regions involved in protein-protein recognition. We propose a mechanism by which the distinct structural organization of the hot spots may contribute to their role in mediating PPI and facilitating binding of structurally diverse small-molecule compounds to protein surfaces.
理解蛋白质-蛋白质相互作用（PPIs）的结构基础可以揭示信号转导和代谢网络的组织和功能，并有助于基于结构设计针对蛋白质-蛋白质界面的配体（药物）。双分子界面上的残基被指定为热点，它们贡献了 PPI 大部分的自由结合能。迄今为止，对于热点的独特功能特性还没有明确的原子解释。我们假设，骨架顺应性可能在蛋白质-蛋白质识别以及小分子化合物与蛋白质表面结合的机制中发挥作用。我们使用定向分子动力学模拟来探索几种模型蛋白中表面暴露残基的骨架顺应性：白细胞介素-2、鼠双微体 2 和增殖细胞核抗原。我们证明，蛋白质表面表现出明显的模式，其中高度不可移动的残基形成定义明确的簇（“稳定性斑块”），与中等至高移动性的区域交替出现。这些“稳定性斑块”往往定位于涉及蛋白质-蛋白质识别的功能重要区域。我们提出了一种机制，即热点的独特结构组织可能有助于它们在介导 PPI 以及促进结构多样的小分子化合物与蛋白质表面结合中的作用。
