Dutta Priyanka, Botlani Mohsen, Varma Sameer
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida , Tampa, Florida 33620, United States.
J Phys Chem B. 2014 Dec 26;118(51):14795-807. doi: 10.1021/jp5089096. Epub 2014 Dec 12.
The dynamical properties of water at protein-water interfaces are unlike those in the bulk. Here we utilize molecular dynamics simulations to study water dynamics in interstitial regions between two proteins. We consider two natural protein-protein complexes, one in which the Nipah virus G protein binds to cellular ephrin B2 and the other in which the same G protein binds to ephrin B3. While the two complexes are structurally similar, the two ephrins share only a modest sequence identity of ∼50%. X-ray crystallography also suggests that these interfaces are fairly extensive and contain exceptionally large amounts of waters. We find that while the interstitial waters tend to occupy crystallographic sites, almost all waters exhibit residence times of less than hundred picoseconds in the interstitial region. We also find that while the differences in the sequence of the two ephrins result in quantitative differences in the dynamics of interstitial waters, the trends in the shifts with respect to bulk values are similar. Despite the high wetness of the protein-protein interfaces, the dynamics of interstitial waters are considerably slower compared to the bulk-the interstitial waters diffuse an order of magnitude slower and have 2-3 fold longer hydrogen bond lifetimes and 2-1000 fold slower dipole relaxation rates. To understand the role of interstitial waters, we examine how implicit solvent models compare against explicit solvent models in producing ephrin-induced shifts in the G conformational density. Ephrin-induced shifts in the G conformational density are critical to the allosteric activation of another viral protein that mediates fusion. We find that in comparison with the explicit solvent model, the implicit solvent model predicts a more compact G-B2 interface, presumably because of the absence of discrete waters at the G-B2 interface. Simultaneously, we find that the two models yield strikingly different induced changes in the G conformational density, even for those residues whose conformational densities in the apo state are unaffected by the treatment of the bulk solvent. Together, these results show that the explicit treatment of interstitial water molecules is necessary for a proper description of allosteric transitions.
蛋白质 - 水界面处水的动力学性质与本体中的不同。在此，我们利用分子动力学模拟来研究两种蛋白质之间间隙区域的水动力学。我们考虑了两种天然的蛋白质 - 蛋白质复合物，一种是尼帕病毒G蛋白与细胞 Ephrin B2 结合，另一种是相同的G蛋白与 Ephrin B3 结合。虽然这两种复合物在结构上相似，但两种 Ephrin 仅具有约50% 的适度序列同一性。X射线晶体学还表明，这些界面相当广泛，并且含有大量的水。我们发现，虽然间隙水倾向于占据晶体学位点，但几乎所有的水在间隙区域的停留时间都小于100皮秒。我们还发现，虽然两种 Ephrin 序列的差异导致间隙水动力学的定量差异，但相对于本体值的位移趋势是相似的。尽管蛋白质 - 蛋白质界面具有高亲水性，但间隙水的动力学与本体相比要慢得多——间隙水的扩散速度慢一个数量级，氢键寿命长2 - 3倍，偶极弛豫速率慢2 - 1000倍。为了理解间隙水的作用，我们研究了在产生 Ephrin 诱导的G构象密度变化方面，隐式溶剂模型与显式溶剂模型的比较情况。Ephrin 诱导的G构象密度变化对于介导融合的另一种病毒蛋白的变构激活至关重要。我们发现，与显式溶剂模型相比，隐式溶剂模型预测的G - B2界面更紧凑，可能是因为G - B2界面不存在离散的水。同时，我们发现即使对于那些在无配体状态下的构象密度不受本体溶剂处理影响的残基，这两种模型在G构象密度上产生的诱导变化也显著不同。总之，这些结果表明，间隙水分子的显式处理对于正确描述变构转变是必要的。
