Mutation profiling, evolution analysis, molecular dynamics simulation, and functional characterization of Omicron...

The ongoing mutation and evolution of SARS-CoV-2 have posed a severe threat to global health, and their functional impact remains to be further characterized. Here, we analyzed the selection pressure from 49 Omicron sub-strains at the gene and amino acid levels. We also examined the impact of mutations on the binding affinity between the receptor binding domain (RBD) and angiotensin-Converting Enzyme 2 (ACE2) and evaluated the immune escape ability of RBD responding to the monoclonal antibodies (mAbs) through molecular dynamics simulation on eight representative Omicron sub-variants (B.1.1.529, BA.2, XBB.1.5, BA.2.86, JN.1, KP.2, KP.3, and KP.3.1.1). We identified 12 positive selection mutation sites on the viral S protein, including 11 mutation sites in the N-terminal domain (NTD) and RBD regions. A large number of accumulated mutation sites led to an increase in the receptor binding affinity of B.1.1.529 and BA.2.86. In particular, the "saltatory" evolution of BA.2.86 reached to its maximum binding affinity. The E484K mutation exhibited the highest binding affinity in the BA.2.86 and its descendants. New mutation sites either did not affect the binding affinity (R346T, L455S and F456L) or decrease the affinity (K356T and Q493E), reflecting the fluctuation of total receptor binding force. Mutations and shortened conformational epitopes on RBD may mediate the immune escape in the variants of BA.2.86. Moreover, we revealed that the ABBV-47D11 monoclonal antibody could widely bind to the RBD mutation sites of various mutant strains. Our findings may help understand the evolution of SARS-CoV-2 variants and develop novel strategies against SARS-CoV-2 infection.