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Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variants Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

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The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and the increased viral fitness by acquiring convergent mutations, suggesting that the immune pressure can promote convergent evolution leading to the sudden acceleration of SARS-CoV-2 evolution. In the current study, we combined structural modeling, extensive microsecond MD simulations and Markov state models to characterize conformational landscapes and identify specific dynamic signatures of the SARS-CoV-2 spike complexes with the host receptor ACE2 for the recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, and BQ.1.1 Omicron variants. Microsecond simulations and Markovian modeling provided a detailed characterization of the conformational landscapes and revealed the increased thermodynamic stabilization of the XBB.1.5 subvariant which is contrasted to more dynamic BQ.1 and BQ.1.1 subvariants. Despite considerable structural similarities, Omicron mutations can induce unique dynamic signatures and specific distributions of conformational states. The results suggested that variant-specific changes of conformational mobility in the functional interfacial loops of the spike receptor binding domain can be fine-tuned through cross-talk between convergent mutations thereby providing an evolutionary path for modulation of immune escape. By combining atomistic simulations and Markovian modeling analysis with perturbation-based approaches, we determined important complementary roles of convergent mutation sites as effectors and receivers of allosteric signaling involved in modulating conformational plasticity at the binding interface and regulating allosteric responses. This study also characterized the dynamics-induced evolution of allosteric pockets in the Omicron complexes that revealed hidden allosteric pockets and suggested that convergent mutation sites could control evolution and distribution of allosteric pockets through modulation of conformational plasticity in the flexible adaptable regions. Through integrative computational approaches, this investigation provides a systematic analysis and comparison of the effects of Omicron subvariants on conformational dynamics and allosteric signaling in the complexes with the ACE2 receptor.