Isin Basak, Doruker Pemra, Bahar Ivet
Polymer Research Center and Chemical Engineering Department, Bogazici University, Bebek 80815, Istanbul, Turkey.
Biophys J. 2002 Feb;82(2):569-81. doi: 10.1016/S0006-3495(02)75422-2.
Influenza virus hemagglutinin (HA), a homotrimeric integral membrane glycoprotein essential for viral infection, is engaged in two biological functions: recognition of target cells' receptor proteins and fusion of viral and endosomal membranes, both requiring substantial conformational flexibility from the part of the glycoprotein. The different modes of collective motions underlying the functional mobility/adaptability of the protein are determined in the present study using an extension of the Gaussian network model (GNM) to treat concerted anisotropic motions. We determine the molecular mechanisms that may underlie HA function, along with the structural regions or residues whose mutations are expected to impede function. Good agreement between theoretically predicted fluctuations of individual residues and corresponding x-ray crystallographic temperature factors is found, which lends support to the GNM elucidation of the conformational dynamics of HA by focusing upon a subset of dominant modes. The lowest frequency mode indicates a global torsion of the HA trimer about its longitudinal axis, accompanied by a substantial mobility at the viral membrane connection. This mode is proposed to constitute the dominant molecular mechanism for the translocation and aggregation of HAs, and for the opening and dilation of the fusion pore. The second and third collective modes indicate a global bending, allowing for a large lateral surface exposure, which is likely to facilitate the close association of the viral and endosomal membranes before pore opening. The analysis of kinetically hot residues, in contrast, reveals a localization of energy centered around the HA2 residue Asp112, which apparently triggers the solvent exposure of the fusion peptide.
流感病毒血凝素（HA）是一种同三聚体整合膜糖蛋白，对病毒感染至关重要，具有两种生物学功能：识别靶细胞的受体蛋白以及病毒膜与内体膜的融合，这两种功能都需要该糖蛋白具有相当大的构象灵活性。本研究使用高斯网络模型（GNM）的扩展来处理协同各向异性运动，确定了该蛋白功能流动性/适应性背后不同的集体运动模式。我们确定了可能是HA功能基础的分子机制，以及其突变预计会阻碍功能的结构区域或残基。发现单个残基的理论预测波动与相应的X射线晶体学温度因子之间有良好的一致性，这通过关注主导模式的一个子集为GNM对HA构象动力学的阐释提供了支持。最低频率模式表明HA三聚体围绕其纵轴的整体扭转，同时在病毒膜连接处有相当大的流动性。该模式被认为是HA转运和聚集以及融合孔开放和扩张的主要分子机制。第二和第三集体模式表明整体弯曲，允许大的侧表面暴露，这可能在孔开放之前促进病毒膜和内体膜的紧密结合。相比之下，对动力学热点残基的分析揭示了能量集中在HA2残基Asp112周围，这显然触发了融合肽的溶剂暴露。
