Sensitivity of Water Dynamics to Biologically Significant Surfaces of Monomeric Insulin: Role of Topology and Electrostatic Interactions
Sensitivity of Water Dynamics to Biologically Significant Surfaces of Monomeric Insulin: Role of Topology and Electrostatic Interactions
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DOI：
10.1021/jp411136w
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发表时间：
2014-04-10
影响因子：
3.3
通讯作者：
Roy, Susmita
中科院分区：
文献类型：
--
作者：
Bagchi, Kushal;Roy, Susmita
除了在人体血液中循环的蛋白质胰岛素的生物活性单体外，该分子还以二聚体和六聚体形式存在，用作储存。胰岛素单体包含两个不同的表面，即二聚体形成表面（DFS）和六聚体形成表面（HFS），它们专门设计用于分别促进二聚体和六聚体的形成。为了表征这两个表面（DFS 和 HFS）附近界面水分子的结构和动力学行为，我们使用显式水对胰岛素进行了原子分子动力学模拟。动力学表征表明，DFS残基与界面水分子之间形成的氢键的结构弛豫比水与HFS之间形成的氢键的结构弛豫更快。此外，DFS 和 HFS 中水分子在蛋白质水合层中的停留时间明显高于迄今为止研究的一些其他蛋白质（例如 HP-36 和溶菌酶）。特别是，我们发现 HFS 附近比 DFS 附近存在更多结构化的水分子，具有更高的停留时间（类似于 300-500 ps）。在 HFS 附近水的 O-H 键向量的相关旋转自时间相关函数的衰减中观察到显着减慢。表面形貌和氨基酸残基的排列共同作用，组织水化层中的水分子，以便为它们提供优选的方向。 HFS 具有较大的极性溶剂可接触表面积和凸出的广泛非极性区域，驱动周围的水分子主要获得向外的氢原子导向的笼形结构。相反，在 DFS 附近，由于疏水表面的平坦曲率和中断的亲水残余排列，周围的水分子获得向内的氢原子定向取向。我们跟踪了几个此类准结合水分子从两个表面的逃逸轨迹，揭示了两个水化层之间的显着差异。
In addition to the biologically active monomer of the protein insulin circulating in human blood, the molecule also exists in dimeric and hexameric forms that are used as storage. The insulin monomer contains two distinct surfaces, namely, the dimer forming surface (DFS) and the hexamer forming surface (HFS), that are specifically designed to facilitate the formation of the dimer and the hexamer, respectively. In order to characterize the structural and dynamical behavior of interfacial water molecules near these two surfaces (DFS and HFS), we performed atomistic molecular dynamics simulations of insulin with explicit water. Dynamical characterization reveals that the structural relaxation of the hydrogen bonds formed between the residues of DFS and the interfacial water molecules is faster than those formed between water and that of the HFS. Furthermore, the residence times of water molecules in the protein hydration layer for both the DFS and HFS are found to be significantly higher than those for some of the other proteins studied so far, such as HP-36 and lysozyme. In particular, we find that more structured water molecules, with higher residence times (similar to 300-500 ps), are present near HFS than those near DFS. A significant slowing down is observed in the decay of associated rotational auto time correlation functions of O-H bond vector of water in the vicinity of HFS. The surface topography and the arrangement of amino acid residues work together to organize the water molecules in the hydration layer in order to provide them with a preferred orientation. HFS having a large polar solvent accessible surface area and a convex extensive nonpolar region, drives the surrounding water molecules to acquire predominantly an outward H-atoms directed, clathrate-like structure. In contrast, near the DFS, the surrounding water molecules acquire an inward H-atoms directed orientation owing to the flat curvature of hydrophobic surface and the interrupted hydrophilic residual alignment. We have followed escape trajectory of several such quasi-bound water molecules from both the surfaces that reveal the significant differences between the two hydration layers.