SARS-CoV-2 Omicron Spike Glycoprotein Receptor Binding Domain Exhibits Super-Binder Ability with ACE2 but not Convalescent Monoclonal Antibody

Background SARS-CoV-2, the causative virus for COVID-19 has now super-mutated into the Omicron ( Om ) variant. On its spike glycoprotein alone, more than 30 substitutions have been characterized with 15 within the receptor binding domain (RBD); It therefore calls to question the transmissibility and antibody escapability of Omicron. This study was setup to investigate the Omicron RBD’s interaction with ACE2 (host receptor) and a SARS-CoV-2 neutralizing monoclonal antibody (mAb). Methods In-silico mutagenesis was used to generate the Om-RBD in complex with ACE2 or mAb from the wildtype. All-atom molecular dynamics (MD) simulation trajectories were analyzed for interaction. Results MD trajectories showed that Omicron RBD has evolved into an efficient ACE2 binder, via pi-pi ( Om -RBD-Y501/ACE2-Y41) and salt-bridge ( Om -RBD-K493/ACE2-Y41) interactions. Conversely, in binding mAb, it has become less efficient (Center of mass distance of RBD from mAb complex, wildtype ≈ 30 Å, Omicron ≈ 41 Å). Disruption of Om -RBD/mAb complex resulted from loose interaction between Om -RBD and the light chain complementarity-determining region residues. Conclusions Omicron is expected to be better transmissible and less efficiently interacting with neutralizing convalescent mAbs. General significance Our results elucidate the mechanisms for higher transmissibility in Omicron variant.