Repository logo
 

Analysis of the Contrasting Pathogenicities Induced by the D222G Mutation in 1918 and 2009 Pandemic Influenza A Viruses.


Change log

Authors

Shang, Cheng 
Whittleston, Chris S 
Sutherland-Cash, Kyle H 
Wales, David J 

Abstract

In 2009, the D222G mutation in the hemagglutinin (HA) glycoprotein of pandemic H1N1 influenza A virus was found to correlate with fatal and severe human infections. Previous static structural analysis suggested that, unlike the H1N1 viruses prevalent in 1918, the mutation did not compromise binding to human α2,6-linked glycan receptors, allowing it to transmit efficiently. Here we investigate the interconversion mechanism between two predicted binding modes in both 2009 and 1918 HAs, introducing a highly parallel intermediate network search scheme to construct kinetically relevant pathways efficiently. Accumulated mutations at positions 183 and 224 that alter the size of the binding pocket are identified with the fitness of the 2009 pandemic virus carrying the D222G mutation. This result suggests that the pandemic H1N1 viruses could gain binding affinity to the α2,3-linked glycan receptors in the lungs, usually associated with highly pathogenic avian influenza, without compromising viability.

Description

Keywords

Binding Sites, Hemagglutinins, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Molecular Dynamics Simulation, Mutation, Protein Structure, Secondary, Protein Structure, Tertiary

Journal Title

J Chem Theory Comput

Conference Name

Journal ISSN

1549-9618
1549-9626

Volume Title

11

Publisher

American Chemical Society (ACS)
Sponsorship
European Research Council (267369)
Engineering and Physical Sciences Research Council (EP/I001352/1)
This work was supported by the ERC and the EPSRC.