Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Proteins. 2012 Nov;80(11):2601-13. doi: 10.1002/prot.24145. Epub 2012 Aug 10.
Vesicular stomatitis virus glycoprotein G (VSV-G) belongs to a new class of viral fusion proteins (Class III). The structure of VSV-G has been solved in two different conformations and fusion is known to be triggered by low pH. To investigate Class III fusion mechanisms, molecular dynamics simulations were performed on the VSV-G prefusion structure in two different protonation states: at physiological pH (pH 7) and low pH present in the endosome (pH 5). Domain IV containing the fusion loops, which need to interact with the target membrane, exhibits the highest mobility. Energetic analyses revealed weakened interaction between Domain IV and the protein core at pH 5, which can be attributed to two pairs of structurally neighboring conserved and differentially protonated residues in the Domain IV-core interface. Energetic calculations also demonstrated that the interaction between the subunits in the core of the trimeric VSV-G is strengthened at pH 5, mainly due to newly formed interactions between the C-terminal loop of Domain II and the N-terminus of the adjacent subunit. A pair of interacting residues in this interface that is affected by differential protonation was shown to be the main effectors of this phenomenon. The results of this study thus enhance the mechanistic understanding of the effects of protonation changes in VSV-G.
水疱性口炎病毒糖蛋白 G（VSV-G）属于一类新型的病毒融合蛋白（Class III）。VSV-G 的结构已在两种不同构象中得到解决，融合已知是由低 pH 值触发的。为了研究 Class III 融合机制，对两种不同质子化状态下的 VSV-G 预融合结构进行了分子动力学模拟：生理 pH 值（pH 7）和内体中的低 pH 值（pH 5）。包含融合环的结构域 IV 表现出最高的流动性，融合环需要与靶膜相互作用。能量分析表明，在 pH 5 时，结构域 IV 与蛋白核心之间的相互作用减弱，这可以归因于结构域 IV-核心界面中两对结构上相邻的保守和差异质子化残基。能量计算还表明，在 pH 5 时，三聚体 VSV-G 核心中亚基之间的相互作用增强，主要是由于结构域 II 的 C 端环和相邻亚基的 N 端之间形成了新的相互作用。该界面中受差异质子化影响的一对相互作用残基被证明是这种现象的主要效应子。因此，这项研究的结果增强了对 VSV-G 质子化变化影响的机制理解。
