Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Eamonn Reading, Valeria Calvaresi*, Dietmar Hammerschmid, Joanna Toporowska, Katherine Doores, Richard T. Bradshaw, Michael Malim, Argyris Politis*, Chloe Roustan, Antoni G Wrobel*, Steve J Gamblin, Donald J. Benton, Ricardo B Parsons

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequent
membrane fusion. It exists in a range of conformations, including a closed state
unable to bind the ACE2 receptor, and an open state that does so but displays more
exposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acid
changes linked to increased virulence and immune evasion. Here, using HDX-MS,
we identified changes in spike dynamics that we associate with the transition from
closed to open conformations, to ACE2 binding, and to specific mutations in VOCs.
We show that the RBD-associated subdomain plays a role in spike opening, whereas
the NTD acts as a hotspot of conformational divergence of VOC spikes driving
immune evasion. Alpha, beta and delta spikes assume predominantly open
conformations and ACE2 binding increases the dynamics of their core helices,
priming spikes for fusion. Conversely, substitutions in omicron spike lead to
predominantly closed conformations, presumably enabling it to escape antibodies. At
the same time, its core helices show characteristics of being pre-primed for fusion
even in the absence of ACE2. These data inform on SARS-CoV-2 evolution and
omicron variant emergence.
Original languageEnglish
JournalNature Communications
Publication statusAccepted/In press - 15 Feb 2023


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