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A glycan gate controls opening of the SARS-CoV-2 spike protein

View ORCID ProfileTerra Sztain, Surl-Hee Ahn, Anthony T. Bogetti, View ORCID ProfileLorenzo Casalino, Jory A. Goldsmith, View ORCID ProfileEvan Seitz, Ryan S. McCool, Fiona L. Kearns, Francisco Acosta-Reyes, Suvrajit Maji, Ghoncheh Mashayekhi, J. Andrew McCammon, Abbas Ourmazd, Joachim Frank, Jason S. McLellan, Lillian T. Chong, View ORCID ProfileRommie E. Amaro
doi: https://doi.org/10.1101/2021.02.15.431212
Terra Sztain
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
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  • ORCID record for Terra Sztain
Surl-Hee Ahn
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
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Anthony T. Bogetti
2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260
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Lorenzo Casalino
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
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  • ORCID record for Lorenzo Casalino
Jory A. Goldsmith
3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712
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Evan Seitz
4Department of Biological Sciences, Columbia University, New York, NY, 10032, USA
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Ryan S. McCool
3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712
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Fiona L. Kearns
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
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Francisco Acosta-Reyes
5Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
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Suvrajit Maji
5Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
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Ghoncheh Mashayekhi
6Department of Physics, University of Wisconsin-Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI 53211, USA
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J. Andrew McCammon
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
7Department of Pharmacology, UC San Diego, La Jolla, CA 92093
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Abbas Ourmazd
6Department of Physics, University of Wisconsin-Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI 53211, USA
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Joachim Frank
4Department of Biological Sciences, Columbia University, New York, NY, 10032, USA
5Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
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Jason S. McLellan
3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712
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Lillian T. Chong
2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260
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  • For correspondence: ramaro@ucsd.edu ltchong@pitt.edu
Rommie E. Amaro
1Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093
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  • ORCID record for Rommie E. Amaro
  • For correspondence: ramaro@ucsd.edu ltchong@pitt.edu
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Abstract

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded “down” to an exposed “up” state in order to bind the human ACE2 receptor and infect cells. While snapshots of the “up” and “down” states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Together with ManifoldEM analysis of cryo-EM data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408, and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://amarolab.ucsd.edu/files/covid19/TRAJECTORIES_continuous_spike_opening_WE_chong_and_amarolab.tar.gz

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 4.0 International license.
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Posted May 17, 2021.
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A glycan gate controls opening of the SARS-CoV-2 spike protein
Terra Sztain, Surl-Hee Ahn, Anthony T. Bogetti, Lorenzo Casalino, Jory A. Goldsmith, Evan Seitz, Ryan S. McCool, Fiona L. Kearns, Francisco Acosta-Reyes, Suvrajit Maji, Ghoncheh Mashayekhi, J. Andrew McCammon, Abbas Ourmazd, Joachim Frank, Jason S. McLellan, Lillian T. Chong, Rommie E. Amaro
bioRxiv 2021.02.15.431212; doi: https://doi.org/10.1101/2021.02.15.431212
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A glycan gate controls opening of the SARS-CoV-2 spike protein
Terra Sztain, Surl-Hee Ahn, Anthony T. Bogetti, Lorenzo Casalino, Jory A. Goldsmith, Evan Seitz, Ryan S. McCool, Fiona L. Kearns, Francisco Acosta-Reyes, Suvrajit Maji, Ghoncheh Mashayekhi, J. Andrew McCammon, Abbas Ourmazd, Joachim Frank, Jason S. McLellan, Lillian T. Chong, Rommie E. Amaro
bioRxiv 2021.02.15.431212; doi: https://doi.org/10.1101/2021.02.15.431212

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