Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk with altered NTD dynamics

  1. Sean M Braet
  2. Theresa SC Buckley
  3. Varun Venkatakrishnan
  4. Kim-Marie A Dam
  5. Pamela J Bjorkman
  6. Ganesh Srinivasan Anand  Is a corresponding author
  1. Pennsylvania State University, United States
  2. California Institute of Technology, United States

Abstract

SARS-CoV-2 emergent variants are characterized by increased viral fitness and each shows multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in subsequent variants. Stabilization preceded altered dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from S mutations detail the evolutionary trajectory of S in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.

Data availability

We have made raw files, ProteinLynx Global Server 3.0 search outputs, and Dynamx files used for HDXMS analysis available through ProteomeXchange. The dataset can be found in the PRIDE repository with identifier PXD040717.

The following data sets were generated

Article and author information

Author details

  1. Sean M Braet

    Department of Chemistry, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Theresa SC Buckley

    Department of Chemistry, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Varun Venkatakrishnan

    Department of Chemistry, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kim-Marie A Dam

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2277-3990
  6. Ganesh Srinivasan Anand

    Department of Chemistry, Pennsylvania State University, University Park, United States
    For correspondence
    gsa5089@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8995-3067

Funding

No external funding was received for this work.

Reviewing Editor

  1. Rina Rosenzweig, Weizmann Institute of Science, Israel

Publication history

  1. Received: August 10, 2022
  2. Preprint posted: August 29, 2022 (view preprint)
  3. Accepted: February 16, 2023
  4. Accepted Manuscript published: March 17, 2023 (version 1)

Copyright

© 2023, Braet et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sean M Braet
  2. Theresa SC Buckley
  3. Varun Venkatakrishnan
  4. Kim-Marie A Dam
  5. Pamela J Bjorkman
  6. Ganesh Srinivasan Anand
(2023)
Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk with altered NTD dynamics
eLife 12:e82584.
https://doi.org/10.7554/eLife.82584

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