Journal of Molecular Modeling

, Volume 18, Issue 9, pp 4355–4366 | Cite as

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 LiuEmail author
  • Xiaojun YaoEmail author
Original Paper


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 α2,3-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 α2,3-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 α2,3-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 α2,3-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.


The altered α-2,3 linked glycan binding to hemagglutinin upon D222G mutation


2009 pandemic influenza A (H1N1) D222G mutation Glycan receptor binding Hemagglutinin (HA) Molecular dynamics simulation Binding free energy calculation 



This work was supported by the National Natural Science Foundation of China (Grant Nos: 20905033 and 21103075). The authors also would like to thank the Super-computing Center of Gansu Province for providing the computing resources.

Supplementary material

894_2012_1423_MOESM1_ESM.doc (102 kb)
ESM1 (DOC 102 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.School of PharmacyLanzhou UniversityLanzhouChina
  2. 2.State Key Laboratory of Applied Organic Chemistry and Department of ChemistryLanzhou UniversityLanzhouChina
  3. 3.Key Lab of Preclinical Study for New Drugs of Gansu ProvinceLanzhou UniversityLanzhouChina

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