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

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(16), P. 5272 - 5296

Published: Aug. 7, 2023

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 evolution leading to sudden acceleration evolution. In current study, we combined structural modeling, microsecond molecular dynamics simulations, Markov state models characterize conformational landscapes identify specific dynamic signatures spike complexes with host receptor ACE2 for recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, BQ.1.1 variants. Microsecond simulations Markovian modeling provided detailed characterization functional states revealed thermodynamic stabilization XBB.1.5 subvariant, which be contrasted more BQ.1 subvariants. Despite considerable similarities, mutations induce unique distributions states. results suggested variant-specific changes mobility in interfacial loops receptor-binding domain protein fine-tuned through crosstalk between could provide an evolutionary path modulation escape. By combining atomistic analysis perturbation-based approaches, determined important complementary roles mutation sites as effectors receivers allosteric signaling involved plasticity regulation communications. This study also hidden pockets control distribution flexible adaptable regions.

Language: Английский

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Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4281 - 4281

Published: April 12, 2024

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with host cell receptor ACE2 and panel diverse class one antibodies. The central objective investigation was to examine molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing antibody evasion variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.5 + L455F/F456L. By combining evolutionary analysis, dynamics simulations, ensemble-based mutational scanning protein residues in complexes ACE2, identified structural stability affinity are consistent results biochemical studies. agreement deep experiments, our quantitative analysis correctly reproduced strong variant-specific effects BA.2 variants. It shown Y453W F456L mutations can enhance when coupled Q493 while these become destabilized R493 position variant. provided rationale mechanism variants, showing role Q493/R493 hotspot modulating between sites L455F lineages. receptors antibodies provide experimental evidence interactions physically proximal Y501, R498, Q493, L455F, determine binding, F486P instrumental mediating broad resistance. supports which impact on is mediated through small group universal hotspots, effect immune could be more variant-dependent modulated by conformationally adaptable regions.

Language: Английский

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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

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2073 - 2073

Published: Oct. 10, 2023

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

Language: Английский

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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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 22, 2023

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

Language: Английский

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Cryo-EM reveals variation in structural motifs within animal SARS-related coronavirus spike proteins

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: July 4, 2023

Abstract SARS-CoV-2 is the third known coronavirus (CoV) that has crossed animal-human barrier in last two decades. However, little structural information exists related to close genetic species within SARS-related coronaviruses. Here, we present three novel CoV spike protein structures solved by single particle cryo-electron microscopy analysis derived from bat (SL-CoV WIV1) and civet (CoV-SZ3, CoV-007) hosts. We report complex glycan trees decorate glycoproteins density for water molecules which facilitated modeling of molecule coordination networks structurally important regions. note conservation fatty acid binding pocket presence a linoleic molecule, are associated with stabilization receptor domains “down” conformation. Additionally, N-terminal biliverdin occupied all structures. Finally, analyzed differences loop motif between coronaviruses infect humans animal described this study, regulate human angiotensin converting enzyme 2 receptor. This study offers framework evaluate origins SARS-CoV-2, risk future cross-species transmission, ability inform pandemic prevention, aid development pan-neutralizing treatments.

Language: Английский

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