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

Shang C, Whittleston CS, Sutherland-Cash KH, Wales DJ - J Chem Theory Comput (2015)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: University Chemical Laboratories , Lensfield Road, Cambridge CB2 1EW, U.K.

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.

No MeSH data available.


Related in: MedlinePlus

Contour plots illustratingthe distribution of the barriers andthe energy changes corresponding to the 3-hydroxyl of Gal, eitherbinding to the side chain of 222D in (a) SC18-WT and (c) NL602-WT,or moving to where it would have bound to the side chain of 222D in(b) SC18–D222G and (d) NL602–D222G with 222G. The heightof the maximum peak in the distributions is scaled to unity. The x axis corresponds to the height of the barrier and the y axis corresponds to the energy difference.
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fig4: Contour plots illustratingthe distribution of the barriers andthe energy changes corresponding to the 3-hydroxyl of Gal, eitherbinding to the side chain of 222D in (a) SC18-WT and (c) NL602-WT,or moving to where it would have bound to the side chain of 222D in(b) SC18–D222G and (d) NL602–D222G with 222G. The heightof the maximum peak in the distributions is scaled to unity. The x axis corresponds to the height of the barrier and the y axis corresponds to the energy difference.

Mentions: Although the G3 displacement is commonto all four cases, the fastest transition paths exhibit systematicdifferences. In SC18-WT, the 3-hydroxyl does not bind to the backbonefirst before binding to the side chain of 222D. In NL602-WT this change,and the binding of the 4-hydroxyl of Gal to the backbone of 222D,occur simultaneously. To compare further we collect all the transitionstates corresponding to steps where the 3-hydroxyl of Gal either bindsto the side chain of 222D in wild type HAs, or moves to the placewhere it would have bound to the side chain of 222D in mutant HAswith 222G. The barrier and energy change distributions for the fourcases are illustrated in the contour plots shown in Figure 4. In SC18-WT, 127 out of 2742 transition statesin the database correspond to this step. The peak value of the distributionis around (0.7, −1.7), corresponding to an energy barrier of 0.7 kcal/mol and an energy differenceof −1.7kcal/mol. The pathways that contribute to this peak all involve breakingthe hydrogen-bond between the 3-hydroxyl of Gal and the backbone of222D. The transition states that contribute to the shoulder peak around(0.5, −2.5) are broadly similar, with insignificant differencesin nearby side chains, for example, the position of the 7-hydroxylof NeuAc. The step in which the 3-hydroxyl of Gal breaks hydrogen-bondswith non-222D residues mainly contributes to the small peak at (3.9,−1.2), as we observed in the fastest path.


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

Shang C, Whittleston CS, Sutherland-Cash KH, Wales DJ - J Chem Theory Comput (2015)

Contour plots illustratingthe distribution of the barriers andthe energy changes corresponding to the 3-hydroxyl of Gal, eitherbinding to the side chain of 222D in (a) SC18-WT and (c) NL602-WT,or moving to where it would have bound to the side chain of 222D in(b) SC18–D222G and (d) NL602–D222G with 222G. The heightof the maximum peak in the distributions is scaled to unity. The x axis corresponds to the height of the barrier and the y axis corresponds to the energy difference.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4547735&req=5

fig4: Contour plots illustratingthe distribution of the barriers andthe energy changes corresponding to the 3-hydroxyl of Gal, eitherbinding to the side chain of 222D in (a) SC18-WT and (c) NL602-WT,or moving to where it would have bound to the side chain of 222D in(b) SC18–D222G and (d) NL602–D222G with 222G. The heightof the maximum peak in the distributions is scaled to unity. The x axis corresponds to the height of the barrier and the y axis corresponds to the energy difference.
Mentions: Although the G3 displacement is commonto all four cases, the fastest transition paths exhibit systematicdifferences. In SC18-WT, the 3-hydroxyl does not bind to the backbonefirst before binding to the side chain of 222D. In NL602-WT this change,and the binding of the 4-hydroxyl of Gal to the backbone of 222D,occur simultaneously. To compare further we collect all the transitionstates corresponding to steps where the 3-hydroxyl of Gal either bindsto the side chain of 222D in wild type HAs, or moves to the placewhere it would have bound to the side chain of 222D in mutant HAswith 222G. The barrier and energy change distributions for the fourcases are illustrated in the contour plots shown in Figure 4. In SC18-WT, 127 out of 2742 transition statesin the database correspond to this step. The peak value of the distributionis around (0.7, −1.7), corresponding to an energy barrier of 0.7 kcal/mol and an energy differenceof −1.7kcal/mol. The pathways that contribute to this peak all involve breakingthe hydrogen-bond between the 3-hydroxyl of Gal and the backbone of222D. The transition states that contribute to the shoulder peak around(0.5, −2.5) are broadly similar, with insignificant differencesin nearby side chains, for example, the position of the 7-hydroxylof NeuAc. The step in which the 3-hydroxyl of Gal breaks hydrogen-bondswith non-222D residues mainly contributes to the small peak at (3.9,−1.2), as we observed in the fastest path.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: University Chemical Laboratories , Lensfield Road, Cambridge CB2 1EW, U.K.

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.

No MeSH data available.


Related in: MedlinePlus