Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles

Cell Host Microbe. 2020 Dec 9;28(6):880-891.e8. doi: 10.1016/j.chom.2020.11.001. Epub 2020 Nov 13.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply 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. Our findings inform on mechanisms of S recognition and conformations for immunogen design.

Keywords: SARS-CoV-2 spike protein; antibody neutralization; real-time conformational dynamics; receptor ACE2; single-molecule FRET.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Viral / immunology
  • COVID-19 / genetics*
  • COVID-19 / immunology
  • COVID-19 / pathology
  • COVID-19 / virology
  • Epitopes / immunology
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / ultrastructure
  • Protein Binding / immunology
  • Protein Conformation*
  • Receptors, Virus / genetics
  • Receptors, Virus / immunology
  • Receptors, Virus / ultrastructure
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / pathogenicity
  • SARS-CoV-2 / ultrastructure*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / ultrastructure*
  • Virion / genetics
  • Virion / ultrastructure
  • Virus Internalization


  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Epitopes
  • Membrane Glycoproteins
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2