SARS-CoV-2 spike (S) mediates viral entry into cells and is critical for vaccine development against COVID-19.

Structural studies have revealed distinct conformations of S, but real-time information that connects these structures, is lacking. In this paper it’s applied single-molecule Fluorescence (Förster) Resonance Energy Transfer (smFRET) imaging to observe conformational dynamics of S on virus particles.

Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor Angiotensin-Converting Enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate.

Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry.

These findings inform on mechanisms of S recognition and conformations for immunogen design.

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