Journal
NATURE CHEMISTRY
Volume 13, Issue 10, Pages 963-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-021-00758-3
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Funding
- National Science Foundation (NSF) [OAC-1818253]
- COVID-19 HPC Consortium Award
- NSF GRFP grant [DGE-1650112]
- National Institutes of Health (NIH) [GM132826]
- NSF RAPID grant [MCB-2032054]
- RCSA Research Corp.
- UC San Diego Moores Cancer Center 2020 SARS-CoV-2 seed grant
- NIH [R01-GM31749, R01-AI127521, R01 GM115805]
- NSF [CHE-1807301]
- NIGMS [R01 GM29169, R35 GM139453]
- US Department of Energy, Office of Science, Basic Energy Sciences [DE-SC0002164]
- US National Science Foundation [STC 1231306, DBI-2029533]
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Through simulations, the study reveals the mechanism of spike protein receptor binding domain (RBD) opening in SARS-CoV-2 infection, highlighting the crucial role of N-glycan in facilitating RBD opening. This research represents a milestone in ensemble pathway simulations and provides a foundation for understanding the fundamental mechanisms of viral entry and infection.
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 to bind the human angiotensin-converting enzyme 2 receptor and infect cells. While snapshots of the 'up' and 'down' states have been obtained by cryo-electron microscopy and cryo-electron tomagraphy, details of the RBD-opening transition evade experimental characterization. Here over 130 mu s of weighted ensemble 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-electron microscopy 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 represents a landmark study for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.
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