Investigating the mutational landscape of the SARS-CoV-2 Omicron variant via ab initio quantum mechanical modeling

SARS-CoV-2 variant "Omicron" B1.1.529 was first identified in South Africa in November 2021. Given the large number of mutations in Omicron's spike protein compared to the original Wuhan strain, its binding efficacy to the ACE2 receptor and its potential to escape antibodies are in the spotlight. Recently, we presented an ab initio quantum mechanical model to characterize the interactions of spike protein's Receptor Binding Domain (RBD) with select antibodies and ACE2 variants. The model identified weak links among the residues constituting interactions with the human ACE2 receptor (hACE2), and also enabled us to characterize in silico mutated RBDs to identify potential Variants of Concern (VOC). In particular, we focused on the role of RBD residue 484 in the interaction of the Delta variant with ACE2 and neutralizing antibodies (nAbs). In this report, we apply our model to the Omicron VOC, and characterize its interaction pattern with hACE2. Our results show that (i) binding affinity with hACE2, compared to Delta, is considerably increased, possibly contributing to increased infectivity. (ii) The interaction pattern between B1.1.529 and hACE2 differs from previous variants by shifting the hot-spot interaction residues on hACE2, and potentially affecting nAbs efficacy. (iii) A K mutation in the RBD residue 484 can further improve Omicron's binding of hACE2 and evasion of nAbs. Finally, we argue that a library of hot-spots for point-mutations can predict binding interaction energies of complex variants. ### Competing Interest Statement The authors have declared no competing interest.