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Characterizing receptor flexibility to predict mutations that lead to human adaptation of influenza hemagglutinin

Huafeng Xu, Timothy Palpant, Cody Weinberger, David E. Shaw
doi: https://doi.org/10.1101/2020.07.15.204982
Huafeng Xu
1D. E. Shaw Research, New York, NY 10036, USA.
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  • For correspondence: huafeng@gmail.com David.Shaw@DEShawResearch.com
Timothy Palpant
1D. E. Shaw Research, New York, NY 10036, USA.
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Cody Weinberger
1D. E. Shaw Research, New York, NY 10036, USA.
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David E. Shaw
1D. E. Shaw Research, New York, NY 10036, USA.
2Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
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  • For correspondence: huafeng@gmail.com David.Shaw@DEShawResearch.com
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Abstract

A key step in the emergence of human pandemic influenza strains has been a switch in the binding preference of the viral glycoprotein hemagglutinin (HA) from avian to human sialic acid receptors (SAs). The conformation of the bound SA varies substantially with HA sequence, and crystallographic evidence suggests that the bound SA is flexible, so it is difficult to predict from crystal structures which mutations are responsible for the change in HA binding preference. We performed molecular dynamics (MD) simulations of SA analogs binding to various HAs, and observed a dynamic equilibrium among structurally diverse receptor conformations, including novel conformations that have not been experimentally observed. Using one such novel conformation, we predicted—and subsequently confirmed with microscale thermophoresis experiments—a set of mutations that substantially increased an HA’s affinity for a human SA analog. This prediction could not have been inferred from existing crystal structures, suggesting that MD-generated HA-SA conformational ensembles could help researchers predict human-adaptive mutations, aiding in the surveillance of emerging pandemic threats.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted July 15, 2020.
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Characterizing receptor flexibility to predict mutations that lead to human adaptation of influenza hemagglutinin
Huafeng Xu, Timothy Palpant, Cody Weinberger, David E. Shaw
bioRxiv 2020.07.15.204982; doi: https://doi.org/10.1101/2020.07.15.204982
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Characterizing receptor flexibility to predict mutations that lead to human adaptation of influenza hemagglutinin
Huafeng Xu, Timothy Palpant, Cody Weinberger, David E. Shaw
bioRxiv 2020.07.15.204982; doi: https://doi.org/10.1101/2020.07.15.204982

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