Probing conformational landscapes of binding and allostery in the SARS-CoV-2 omicron variant complexes using microsecond atomistic simulations and perturbation-based profiling approaches: hidden role of omicron mutations as modulators of allosteric signaling and epistatic relationships.

In this study, we systematically examine the conformational dynamics, binding and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 spike protein complexes with the ACE2 host receptor using molecular dynamics simulations and perturbation-based network profiling approaches. Microsecond atomistic simulations provided a detailed characterization of the conformational landscapes and revealed the increased thermodynamic stabilization of the BA.2 variant which can be contrasted with the BA.4/BA.5 variants inducing a significant mobility of the complexes. Using the dynamics-based mutational scanning of spike residues, we identified structural stability and binding affinity hotspots in the Omicron complexes. Perturbation response scanning and network-based mutational profiling approaches probed the effect of the Omicron mutations on allosteric interactions and communications in the complexes. The results of this analysis revealed specific roles of Omicron mutations as conformationally plastic and evolutionary adaptable modulators of binding and allostery which are coupled to the major regulatory positions through interaction networks. Through perturbation network scanning of allosteric residue potentials in the Omicron variant complexes performed in the background of the original strain, we characterized regions of epistatic couplings that are centered around the binding affinity hotspots N501Y and Q498R. Our results dissected the vital role of these epistatic centers in regulating protein stability, efficient ACE2 binding and allostery which allows for accumulation of multiple Omicron immune escape mutations at other sites. Through integrative computational approaches, this study provides a systematic analysis of the effects of Omicron mutations on thermodynamics, binding and allosteric signaling in the complexes with ACE2 receptor.