Molecular mechanism of the enhanced virulence of 2009 pandemic Influenza A (H1N1) virus from D222G mutation in the hemagglutinin: a molecular modeling study
Molecular mechanism of the enhanced virulence of 2009 pandemic Influenza A (H1N1) virus from D222G mutation in the hemagglutinin: a molecular modeling study
复制标题
2009年大流行甲型H1N1流感病毒血凝素D222G突变毒力增强的分子机制：分子模型研究
DOI：
10.1007/s00894-012-1423-2
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发表时间：
2012-09-01
影响因子：
2.2
通讯作者：
Yao, Xiaojun
中科院分区：
文献类型：
--
作者：
Pan, Dabo;Xue, Weihua;Yao, Xiaojun
血凝素(HA)的D222G突变特别令人感兴趣，因为它与2009年甲型H1N1流感病毒的毒力增强密切相关，因为它与α2，3连接的唾液酸糖受体结合亲和力增强。然而，对于这种增强毒力的分子机制仍缺乏详细的了解。在这里，通过分子动力学模拟和结合自由能计算，通过研究1个α-2，3-连接唾液酸聚糖(序列：SIA-GAL-NAG)与野生型和D222G突变的HA的相互作用，来探讨HA与D222G突变后的糖链受体结合的变化机制。基于分子力学广义玻恩表面积(MM-GBSA)方法的结合自由能计算表明，D222G突变的HA与所研究的α-2，3-连接的多糖具有比野生型更强的结合亲和力。这与实验结果是一致的。D222G突变体结合自由能的增加主要来自Gln223的能量贡献。结构分析证明，受体结合区(RBD)的静电势改变和220环的灵活性增加是导致HA与α2，3连接的唾液酸聚糖亲和力增强的根本原因。本研究结果对流感病毒的受体识别机制和致病性有了更深入的了解，对于针对流感病毒进入过程的结构类抑制剂的设计具有一定的参考价值。
D222G mutation of the hemagglutinin (HA) is of special interest because of its close association with the enhanced virulence of 2009 pandemic influenza A (H1N1) virus through the increased binding affinity to alpha 2,3-linked sialylated glycan receptors. However, there is still a lack of detailed understanding about the molecular mechanism of this enhanced virulence. Here, molecular dynamics simulation and binding free energy calculation were performed to explore the altered glycan receptor binding mechanism of HA upon the D222G mutation by studying the interaction of one alpha 2,3-linked sialylglycan (sequence: SIA-GAL-NAG) with the wild type and D222G mutated HA. The binding free energy calculation based on the molecular mechanics generalized Born surface area (MM-GBSA) method indicates that the D222G mutated HA has a much stronger binding affinity with the studied alpha 2,3-linked glycan than the wild type. This is consistent with the experimental result. The increased binding free energy of D222G mutant mainly comes from the increased energy contribution of Gln223. The structural analysis proves that the altered electrostatic potential of receptor binding domain (RBD) and the increased flexibility of 220-loop are the essential reasons leading to the increased affinity of HA to alpha 2,3-linked sialic acid glycans. The obtained results of this study have allowed a deeper understanding of the receptor recognition mechanism and the pathogenicity of influenza virus, which will be valuable to the structure-based inhibitors design targeting influenza virus entry process.