Molecular switches regulating the potency and immune evasiveness of SARS-CoV-2 spike protein

What enabled SARS-CoV-2, but not other coronaviruses, to cause a global pandemic? Here we investigated key structural determinants of the pandemic. Using SARS-CoV-1 and bat RaTG13-CoV as comparisons, we identified two molecular switches that regulate the conformations of SARS-CoV-2 spike protein: (i) a furin motif loop turns SARS-CoV-2 spike from a closed conformation to a mixture of open and closed conformations, and (ii) a K417V mutation turns SARS-CoV-2 spike from mixed conformations to an open conformation. We showed that the open conformation favors viral potency by exposing the RBD for receptor binding and viral entry, while the closed conformation supports viral immune evasion by hiding the RBD from neutralizing antibodies. Hence SARS-CoV-2 spike has evolved to reach a balance between potency and immune evasiveness, which contributes to the pandemic spread of SARS-CoV-2.The dynamics between viral potency and invasiveness is likely to further evolve, providing insights into future evolution of SARS-CoV-2.