Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers: Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

Verkhivker, Gennady M.; Alshahrani, Mohammed; Gupta, Grace

doi:10.3390/ijms24076642

Cited by 3 publications

(3 citation statements)

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“…75−81 A comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the different functional states of S trimers for BA.1, BA.2, and BA.2.75 variants showed that Omicron mutations may evolve by targeting vulnerable sites of conformational adaptability to elicit immune escape while maintaining their control on balancing protein stability and functional fitness through robust allosteric communications with the stability hotspots. 82 By combining atomistic simulations and a community-based network model of epistatic couplings, we found that convergent Omicron mutations such as G446S (BA.2.75, BA.2.75.2, XBB), F486V (BA.4, BA.5, BQ.1, BQ.1.1), F486S, F490S (XBB.1), F486P (XBB.1.5) can display epistatic relationships with the major stability and binding affinity hotspots which may allow for the observed broad antibody resistance. 83 In the current study, we perform multiple microsecond MD simulations and Markov state model (MSM) analysis to characterize conformational landscapes and identify specific dynamic signatures of the SARS-CoV-2 S RBD-ACE2 complexes for the recently emerged XBB.1, XBB.1.5, BQ.1, and BQ.1.1 Omicron variants.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The linkage between conformational dynamics and allosteric modulation of SARS-CoV-2 S in the absence or presence of ligands was established in an smFRET imaging assay, showing the presence of long-range allosteric control of the RBD equilibrium, which in turn regulates the exposure of the binding site and antibody binding . Our studies used integrative computational modeling approaches to reveal that the S protein could function as an allosteric regulatory machinery controlled by stable allosteric hotspots acting as drivers and regulators of spike activity. − A comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the different functional states of S trimers for BA.1, BA.2, and BA.2.75 variants showed that Omicron mutations may evolve by targeting vulnerable sites of conformational adaptability to elicit immune escape while maintaining their control on balancing protein stability and functional fitness through robust allosteric communications with the stability hotspots . By combining atomistic simulations and a community-based network model of epistatic couplings, we found that convergent Omicron mutations such as G446S (BA.2.75, BA.2.75.2, XBB), F486V (BA.4, BA.5, BQ.1, BQ.1.1), F486S, F490S (XBB.1), F486P (XBB.1.5) can display epistatic relationships with the major stability and binding affinity hotspots which may allow for the observed broad antibody resistance …”

Section: Introductionmentioning

confidence: 99%

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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 Variant Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

Xiao,

Alshahrani,

Gupta

et al. 2023

J. Chem. Inf. Model.

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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.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Xiao,

Alshahrani,

Gupta

et al. 2023

J. Chem. Inf. Model.

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“…Despite mutational differences between BA.1, BA.2 and BA.2.75 lineages, the recent study of the electrostatic potentials showed a strong positive electrostatic surface in the S-RBD regions for these variants supporting the mechanism in which the enhanced electropositive character of the RBD variants is strongly related with their enhanced capacity for the virus transmission [ 54 ]. Our analysis also suggested that the evolution of the SARS-CoV-2 virus and the emergence of recombinant variants may have signaled a certain critical plateau of electrostatic positively charged RBD distribution that is optimal to complement ACE2 electrostatic potential, and convergent mutations could have emerged to balance multiple tradeoffs rather than progressively improving the RBD-ACE2 binding affinities [ 55 ].…”

Section: Introductionmentioning

confidence: 99%

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

Alshahrani,

Gupta,

Xiao

et al. 2023

Viruses

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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.

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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

Xiao

Alshahrani

Gupta

et al. 2023

Preprint

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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.For Table of Contents Use Only

show abstract

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers: Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

Cited by 3 publications

References 126 publications

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

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

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

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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