Van't Hoff Institute for Molecular Sciences , Universiteit van Amsterdam , Science Park 904 , 1090 GD Amsterdam , The Netherlands.
J Phys Chem B. 2019 Mar 7;123(9):1883-1895. doi: 10.1021/acs.jpcb.8b10005. Epub 2019 Feb 27.
Association and dissociation of proteins are fundamental processes in nature. Although simple to understand conceptually, the details of the underlying mechanisms and role of the solvent are poorly understood. Here, we investigate the dissociation of the hydrophilic β-lactoglobulin dimer by employing transition path sampling. Analysis of the sampled path ensembles reveals a variety of mechanisms: (1) a direct aligned dissociation (2) a hopping and rebinding transition followed by unbinding, and (3) a sliding transition before unbinding. Reaction coordinate and transition-state analysis predicts that, besides native contact and neighboring salt-bridge interactions, solvent degrees of freedom play an important role in the dissociation process. Bridging waters, hydrogen-bonded to both proteins, support contacts in the native state and nearby lying transition-state regions, whereas they exhibit faster dynamics in further lying transition-state regions, rendering the proteins more mobile and assisting in rebinding. Analysis of the structure and dynamics of the solvent molecules reveals that the dry native interface induces enhanced populations of both disordered hydration water near hydrophilic residues and tetrahedrally ordered hydration water nearby hydrophobic residues. Although not exhaustive, our sampling of rare unbiased reactive molecular dynamics trajectories enhances the understanding of protein dissociation via complex pathways including (multiple) rebinding events.
蛋白质的缔合和解离是自然界的基本过程。尽管从概念上理解起来很简单，但对潜在机制和溶剂作用的细节却知之甚少。在这里，我们通过过渡路径采样来研究亲水性β-乳球蛋白二聚体的解离。对采样路径集的分析揭示了多种机制：（1）直接对齐的解离；（2）跳跃和再结合跃迁，然后是解络；（3）解络前的滑动跃迁。反应坐标和过渡态分析预测，除了天然接触和相邻盐桥相互作用外，溶剂自由度在解离过程中起着重要作用。桥接水与两种蛋白质都形成氢键，支持天然状态和附近的过渡态区域的接触，而在更远的过渡态区域，它们表现出更快的动力学，使蛋白质更具流动性并有助于再结合。对溶剂分子的结构和动力学的分析表明，干燥的天然界面会导致亲水性残基附近的无序水合水和疏水性残基附近的四面体有序水合水的含量增加。尽管不是详尽无遗的，但我们对无偏反应性分子动力学轨迹的抽样增强了对通过包括（多次）再结合事件在内的复杂途径进行蛋白质解离的理解。
