Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding Sites

Abstract

A significant body of experimental structures of the SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and emergence of druggable cryptic pockets. Understanding of the interplay of conformational dynamics changes induced by Omicron variants and identification of cryptic dynamic binding pockets in the S protein are of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study we explore conformational landscapes and characterize the universe of cryptic binding pockets in multiple open and closed functional spike states of the Omicron BA.1 and BA.2 variants. By using a combination of atomistic simulations, dynamics network analysis, and allostery-guided network screening of cryptic pockets in the conformational ensembles of BA.1 and BA.2 spike conformations, we identified all experimentally known allosteric sites and discovered significant variant-specific differences in the distribution of cryptic binding sites in the BA.1 and BA.2 trimers. This study provided in-depth structural analysis of the predicted allosteric site in the context of all available experimental information, revealing a critical role and effect of conformational plasticity on the distribution and function of allosteric binding sites. The results detailed how mutational and conformational changes in the BA.1 and BA.2 pike trimers can modulate the functional role of druggable allosteric pockets across different functional regions of the spike protein. The results of this study are particularly significant for understanding the universe of cryptic bindings sites and variant-specific preferences for druggable pockets. Exploring predicted druggable sites can present a new and previously underappreciated opportunity for therapeutic intervention of Omicron variants through conformation-selective and variant-specific targeting of functional sites involved in allosteric changes.