SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy

• Published in: mBio Vol. 13; no. 1; p. e0322721
• Main Authors: Yang, Ziwei, Han, Yang, Ding, Shilei, Shi, Wei, Zhou, Tongqing, Finzi, Andrés, Kwong, Peter D, Mothes, Walther, Lu, Maolin
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 22.02.2022
• Subjects: Biological Evolution; conformational dynamics; COVID-19; COVID-19 Vaccines; Humans; Protein Binding; Protein Conformation; Receptors, Virus - metabolism; Research Article; SARS-CoV-2 - genetics; SARS-CoV-2 variants; single-molecule FRET; spike glycoprotein; Spike Glycoprotein, Coronavirus - metabolism; structure; Virology; SARS-CoV-2 variants; single-molecule FRET; spike glycoprotein; conformational dynamics; structure
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.03227-21

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) harbor mutations in the spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses, with structural studies of soluble S variants revealing an increased propensity toward conformations accessible to the human angiotensin-converting enzyme 2 (hACE2) receptor. However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster resonance energy transfer (smFRET) studies of critical mutations observed in VOCs, including D614G and E484K, in the context of virus particles. Investigated variants predominately occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited slower transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population. SARS-CoV-2 surface S glycoprotein-the target of antibodies and vaccines-is responsible for binding to the cellular receptor hACE2. The interactions between S and hACE2 trigger structural rearrangements of S from closed to open conformations prerequisite for virus entry. Under the selection pressure imposed by adaptation to the human host and increasing vaccinations and convalescent patients, SARS-CoV-2 is evolving and has adopted numerous mutations on S variants. These promote virus spreading and immune evasion, partially by increasing the propensity of S to adopt receptor-binding competent open conformations. Here, we determined a time dimension, using smFRET to delineate the temporal prevalence of distinct structures of S in the context of virus particles. We present the first experimental evidence of decelerated transition dynamics from the open state, revealing increased stability of S open conformations to be part of the SARS-CoV-2 adaption strategies.