Evolutionary progression of collective mutations in Omicron sub-lineages towards efficient RBD-hACE2: allosteric communications between and within viral and human proteins

Abstract The interaction between the Spike (S) protein of SARS-CoV-2 and the human angiotensin converting enzyme 2 (hACE2) is essential for infection, and is a target for neutralizing antibodies. Consequently, selection of mutations in the S protein is expected to be driven by the impact on the interaction with hACE2 and antibody escape. Here, for the first time, we systematically characterized the collective effects of mutations in each of the Omicron sub-lineages (BA.1, BA.2, BA.3 and BA.4) on both the viral S protein receptor binding domain (RBD) and the hACE2 protein using post molecular dynamics studies and dynamic residue network (DRN) analysis. Our analysis suggested that Omicron sub-lineage mutations result in altered physicochemical properties that change conformational flexibility compared to the reference structure, and may contribute to antibody escape. We also observed changes in the hACE2 substrate binding groove in some sub-lineages. Notably, we identified unique allosteric communication paths in the reference protein complex formed by the DRN metrics betweenness centrality and eigencentrality hubs, originating from the RBD core traversing the receptor binding motif of the S protein and the N-terminal domain of the hACE2 to the active site. We showed allosteric changes in residue network paths in both the RBD and hACE2 proteins due to Omicron sub-lineage mutations. Taken together, these data suggest progressive evolution of the Omicron S protein RBD in sub-lineages towards a more efficient interaction with the hACE2 receptor which may account for the increased transmissibility of Omicron variants.