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Previous static structural analysis suggested that, unlike the H1N1 viruses prevalent in 1918, the mutation did not compromise binding to human \u03b12,6-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 \u03b12,3-linked glycan receptors in the lungs, usually associated with highly pathogenic avian influenza, without compromising viability.<\/jats:p>","DOI":"10.1021\/ct5010565","type":"journal-article","created":{"date-parts":[[2015,3,24]],"date-time":"2015-03-24T16:53:28Z","timestamp":1427216008000},"page":"2307-2314","source":"Crossref","is-referenced-by-count":3,"title":["Analysis\nof the Contrasting Pathogenicities Induced\nby the D222G Mutation in 1918 and 2009 Pandemic Influenza A Viruses"],"prefix":"10.1021","volume":"11","author":[{"given":"Cheng","family":"Shang","sequence":"first","affiliation":[{"name":"University Chemical Laboratories , Lensfield Road , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris S.","family":"Whittleston","sequence":"additional","affiliation":[{"name":"University Chemical Laboratories , Lensfield Road , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle H.","family":"Sutherland-Cash","sequence":"additional","affiliation":[{"name":"University Chemical Laboratories , Lensfield Road , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Wales","sequence":"additional","affiliation":[{"name":"University Chemical Laboratories , Lensfield Road , ,","place":["Cambridge, U.K., CB2 1EW"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,3,24]]},"reference":[{"key":"2026090303015231000_cit1","doi-asserted-by":"crossref","first-page":"e92789","DOI":"10.1371\/journal.pone.0092789","volume":"9","author":"Resende","year":"2014","journal-title":"PLoS One"},{"key":"2026090303015231000_cit2","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1128\/JVI.06322-11","volume":"86","author":"Xu","year":"2012","journal-title":"J. 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