Comparative Analysis of Conformational Dynamics and Systematic Characterization of Cryptic Pockets in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 Spike Complexes with the ACE2 Host Receptor: Confluence of Binding and Structural Plasticity in Mediating Networks of Conserved Allosteric Sites

Abstract

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes with the ACE2 receptor complemented atomistic studies and enabled an in-depth analysis of mutational and binding effects on conformational dynamic and functional adaptability of the Omicron variants. Despite considerable structural similarities, Omicron variants BA.2, BA.2.75 and XBB.1 can induce unique conformational dynamic signatures and specific distributions of the conformational states. Using conformational ensembles of the SARS-CoV-2 Omicron spike trimer complexes with ACE2, we conducted a comprehensive cryptic pocket screening to examine the role of Omicron mutations and ACE2 binding on the distribution and functional mechanisms of the emerging allosteric binding sites. This analysis captured all experimentally known allosteric sites and discovered networks of inter-connected and functionally relevant allosteric sites that are governed by variant-sensitive conformational adaptability of the SARS-CoV-2 spike structures. The results detailed how ACE2 binding and Omicron mutations in the BA.2, BA.2.75 and XBB.1 spike complexes modulate the distribution of conserved and druggable allosteric pockets harboring functionally important regions. The results are significant for understanding the functional roles of druggable cryptic pockets that can be used for allostery-mediated therapeutic intervention targeting conformational states of the Omicron variants.

Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling

“…75 The recent structural and computational studies suggested that Omicron mutations have significant and often variant-specific effect on mediating conformational dynamics changes in the S protein including allosterically induced plasticity at the remote regions leading to the formation and evolution of druggable cryptic pockets. 76,77 lineages proceeded through diverse mechanisms including but not limited to simple and complex recombination, antigenic drift and convergent evolution that led to convergent immune-escape mutations and effective evasion of neutralizing antibodies. 56 The recent proliferation of several lineages with similar replicative fitness and significant antigenic distance from each other was marked by the recent emergence of BA.…”

Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

“…Our recent studies combined multiscale simulations with network-based modeling to reveal that the S protein can function as a functionally adaptable allosterically regulated machine that exploits the plasticity of allosteric centers to fine-tune responses to antibody binding [41][42][43][44][45]. Recent computational studies in our laboratory also showed that SARS-CoV-2 S Omicron mutations have variant-specific effects on conformational dynamics changes including allosterically induced plasticity at the remote regions leading to the formation and evolution of druggable cryptic pockets [46,47].…”

Predicting Functional Conformational Ensembles and Binding Mechanisms of Convergent Evolution for SARS-CoV-2 Spike Omicron Variants Using AlphaFold2 Sequence Scanning Adaptations and Molecular Dynamics Simulations

“…67 Recent computational studies suggested that Omicron mutations have variant-specific effect on conformational dynamics changes in the S protein including allosterically induced plasticity at the remote regions leading to the formation and evolution of druggable cryptic pockets. 68,69…”