Complex Mutation Pattern of Omicron BA.2: Evading Antibodies without Losing Receptor Interactions

Abstract

BA.2, a sublineage of Omicron BA.1, is now prominent in many parts of the world. Early reports have indicated that BA.2 is more infectious than BA.1. To gain insight into BA.2 mutation profile and the resulting impact of mutations on interactions with receptor and/or monoclonal antibodies, we analyzed available sequences, structures of Spike/receptor and Spike/antibody complexes, and conducted molecular dynamics simulations. The results showed that BA.2 had 50 high-prevalent mutations, compared to 48 in BA.1. Additionally, 17 BA.1 mutations were not present in BA.2. Instead, BA.2 had 19 unique mutations and a signature Delta variant mutation (G142D). The BA.2 had 28 signature mutations in Spike, compared to 30 in BA.1. This was due to two revertant mutations, S446G and S496G, in the receptor-binding domain (RBD), making BA.2 somewhat similar to Wuhan-Hu-1 (WT), which had G446 and G496. The molecular dynamics simulations showed that the RBD consisting of G446/G496 was more stable than S446/S496 containing RBD. Thus, our analyses suggested that BA.2 evolved with novel mutations (i) to maintain receptor binding similar to WT, (ii) evade the antibody binding greater than BA.1, and (iii) acquire mutation of the Delta variant that may be associated with the high infectivity.

Atomistic Simulations and Network-Based Energetic Profiling of Binding and Allostery in the SARS-CoV-2 Spike Omicron BA.1, BA.1.1, BA.2 and BA.3 Subvariant Complexes with the Host Receptor: Revealing Hidden Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Long-Range Communication with Allosteric Pockets

“…Sequence and structure-based computational analysis of the Omicron BA.2 showed the reversed G446/G496 combination makes BA.2 more stable than Omicron BA.1 featuring S446/S496 mutations. The study concluded that Omicron BA.2 subvariant may have evolved to maintain ACE2 binding similar to the original strain while promoting more efficient antibody evasion highlighting how complex pattern of mutations balances these conflicting factors [64]. By employing the conformational ensembles of the S-RBD Omicron variant complexes with ACE2 we recently performed simulations and mutational scanning of the interfacial RBD residues showing that N501Y is the critical binding affinity hotspot in the S Omicron RBD complex with ACE2, while hotspots Q493R, G496S, Q498R anchor the key interfacial clusters responsible for binding with ACE2 [65].…”

Omicron BA.2 Lineage, the “Stealth” Variant: Is It Truly a Silent Epidemic? A Literature Review

“…Whole-genome sequencing (WGS) analysis identified a total of 50 mutations within the S-protein in the BA.2 variant, compared to 48 mutations present in Omicron BA.1. Additionally, 17 mutations of BA.1 were not present in BA.2 [5]. The differences between the BA.1 and BA.2 lineages and other VOCs are consistent: 28 mutations and 50 amino acids make them approximately twice as different compared to the other four VOCs (Alpha, Beta, Gamma, and Delta) that diverge from the original wild-type SARS-CoV-2 strain [4,5].…”

“…Additionally, 17 mutations of BA.1 were not present in BA.2 [5]. The differences between the BA.1 and BA.2 lineages and other VOCs are consistent: 28 mutations and 50 amino acids make them approximately twice as different compared to the other four VOCs (Alpha, Beta, Gamma, and Delta) that diverge from the original wild-type SARS-CoV-2 strain [4,5]. Moreover, 17 amino acids, 3 deletions, and 1 insertion (many of them in the N-terminal domain (NTD) and in the receptor-binding domain (RBD)) distinguish BA.1 and BA.2 [6].…”

“…Focusing on the S gene, BA.2 shares 21 mutations with BA.1, but it also has 8 unique mutations prevalently clustered in the N-terminal domain (NTD) and in the receptorbinding domain (RBD) [3]. Compared with BA.1, S371L, G446S, and G496S are deleted in BA.2, whereas S371F, T376A, D405N, and R408S are added [5,9]. The interactions between these unique variations may be responsible for the peculiarities of the BA-2 lineage (Table 1).…”

Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

“…It could be possible that the surface exposed residues within sub variant BA.2 bind more strongly to the ACE2 receptor than omicron variant. This sub variant may have antibody neutralizing escape mutants and thus, may emerge as a strong form of the virus [29,30].…”