Progressive membrane-binding mechanism of SARS-CoV-2 variant spike proteins

Membrane recognition by viral spike proteins is critical for infection. Here we show the host cell membrane-binding surfaces of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike variants Alpha, Beta, Gamma, Delta, Epsilon, Kappa, and Omicron as well as SARS-CoV-1 and pangolin and bat relatives. They show increases in membrane binding propensities over time, with all spike head mutations in variants, and particularly BA.1, impacting the protein's affinity to cell membranes. Comparison of hundreds of structures yields a progressive model of membrane docking in which spike protein trimers shift from initial perpendicular stances to increasingly tilted positions that draw viral particles alongside host cell membranes before optionally engaging angiotensin-converting enzyme 2 (ACE2) receptors. This culminates in the assembly of the symmetric fusion apparatus, with enhanced membrane interactions of variants explaining their unique cell fusion capacities and COVID-19 disease transmission rates.