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SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy

Ziwei Yang, Yang Han, Shilei Ding, Andrés Finzi, Walther Mothes, View ORCID ProfileMaolin Lu
doi: https://doi.org/10.1101/2021.10.11.463956
Ziwei Yang
1Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA
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Yang Han
2Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, TX, USA
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Shilei Ding
3Centre de Recherche du CHUM (CRCHUM), Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada
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Andrés Finzi
3Centre de Recherche du CHUM (CRCHUM), Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada
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Walther Mothes
1Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA
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Maolin Lu
2Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, TX, USA
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  • ORCID record for Maolin Lu
  • For correspondence: maolin.lu@uthct.edu
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ABSTRACT

SARS-CoV-2 variants of concern harbor mutations in the Spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses. Structural studies of soluble S variants have revealed an increased propensity towards conformations accessible to receptor human Angiotensin-Converting Enzyme 2 (hACE2). However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster Resonance Energy Transfer (smFRET) studies of S variants containing critical mutations, including D614G and E484K, in the context of virus particles. Investigated variants predominantly occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited decelerated transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population.

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. All rights reserved. No reuse allowed without permission.
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Posted October 12, 2021.
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SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy
Ziwei Yang, Yang Han, Shilei Ding, Andrés Finzi, Walther Mothes, Maolin Lu
bioRxiv 2021.10.11.463956; doi: https://doi.org/10.1101/2021.10.11.463956
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SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy
Ziwei Yang, Yang Han, Shilei Ding, Andrés Finzi, Walther Mothes, Maolin Lu
bioRxiv 2021.10.11.463956; doi: https://doi.org/10.1101/2021.10.11.463956

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