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

• Published in: Journal of chemical information and modeling 2023-08, Vol.63 (16), p.5272-5296
• Main Authors: Xiao, Sian, Alshahrani, Mohammed, Gupta, Grace, Tao, Peng, Verkhivker, Gennady
• Format: Article
• Language: English
• Subjects: Communication; Computational Biochemistry; Convergence; COVID-19; Crosstalk; Dynamic structural analysis; Evolution; Humans; Modelling; Modulation; Molecular dynamics; Mutation; Perturbation; Plastic properties; Receptors; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Signatures; Simulation
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.3c00778

The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and 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, microsecond molecular dynamics 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 functional conformational states and revealed the increased thermodynamic stabilization of the XBB.1.5 subvariant, which can be 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 the conformational states. The results suggested that variant-specific changes of the conformational mobility in the functional interfacial loops of the receptor-binding domain in the SARS-CoV-2 spike protein can be fine-tuned through crosstalk between convergent mutations which could provide 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 modulation of conformational plasticity and regulation of allosteric communications. This study also 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.