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

Creators: Braet, Sean M.; Buckley, Theresa S. C.; Venkatakrishnan, Varun; Dam, Kim-Marie A.; Bjorkman, Pamela J.; Anand, Ganesh

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.

Additional Information

© 2023, Braet, Buckley, Venkatakrishnan et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Startup funding from the Pennsylvania State University (PSU) to GSA. We thank Rosa Viner (Thermo Scientific, San Jose, CA) for S glycan analysis. We thank Susan Marqusee (University of California Berkley, CA) for discussions and help with revision. No external funding was received for this work. 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.

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