Molecular mechanism of the enhanced virulence of 2009 pandemic Influenza A (H1N1) virus from D222G mutation in the hemagglutinin: A molecular modeling study

Dabo Pan, Weihua Xue, Xiaoting Wang, Jingjing Guo, Huanxiang Liu, Xiaojun Yao

研究成果: Article同行評審

16 引文 斯高帕斯(Scopus)

摘要

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 a2,3-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 a2,3-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 a2,3-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 a2,3-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.

原文English
頁(從 - 到)4355-4366
頁數12
期刊Journal of Molecular Modeling
18
發行號9
DOIs
出版狀態Published - 9月 2012
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