Abriata Luciano A, Dal Peraro Matteo
Laboratory for Biomolecular Modeling, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL) and Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Sci Rep. 2015 May 29;5:10549. doi: 10.1038/srep10549.
Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin's noncovalent dimerization equilibrium to assess the potential of atomistic simulations to reproduce reversible protein-protein binding, by running submicrosecond simulations of systems with multiple copies of the protein at millimolar concentrations. The simulations essentially fail because they lead to aggregates, yet they reproduce some specificity in the binding interfaces as observed in known covalent and noncovalent ubiquitin dimers. Following similar observations in literature we hint at electrostatics and water descriptions as the main liable force field elements, and propose that their optimization should consider observables relevant to multi-protein systems and unfolded proteins. Within limitations, analysis of binding events suggests salient features of protein-protein recognition and binding, to be retested with improved force fields. Among them, that specific configurations of relative direction and orientation seem to trigger fast binding of two molecules, even over 50 Å distances; that conformational selection can take place within surface-to-surface distances of 10 to 40 Å i.e. well before actual intermolecular contact; and that establishment of contacts between molecules further locks their conformations and relative orientations.
蛋白质-蛋白质的识别与结合受扩散、非共价力和构象灵活性的支配，它们相互交织，只有分子动力学模拟才能在高分辨率下解析。在这里，我们利用泛素的非共价二聚化平衡，通过对毫摩尔浓度下含有多个蛋白质拷贝的系统进行亚微秒模拟，来评估原子模拟再现可逆蛋白质-蛋白质结合的潜力。模拟基本上失败了，因为它们导致了聚集体的形成，然而，它们在结合界面上再现了一些特异性，这在已知的共价和非共价泛素二聚体中也有观察到。继文献中的类似观察结果之后，我们指出静电作用和水的描述是主要的有问题的力场元素，并建议对它们的优化应考虑与多蛋白系统和未折叠蛋白相关的可观测值。在一定限制范围内，对结合事件的分析揭示了蛋白质-蛋白质识别与结合的显著特征，有待用改进的力场重新检验。其中包括，相对方向和取向的特定构型似乎能触发两个分子的快速结合，即使在超过50 Å的距离上也是如此；构象选择可以在10至40 Å的表面到表面距离内发生，即在实际分子间接触之前很久；分子间接触的建立进一步锁定了它们的构象和相对取向。
