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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Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(5), P. 1413 - 1428

Published: Feb. 24, 2023

Allosteric mechanisms are commonly employed regulatory tools used by proteins to orchestrate complex biochemical processes and control communications in cells. The quantitative understanding characterization of allosteric molecular events among major challenges modern biology require integration innovative computational experimental approaches obtain atomistic-level knowledge the states, interactions, dynamic conformational landscapes. growing body studies empowered emerging artificial intelligence (AI) technologies has opened up new paradigms for exploring learning universe protein allostery from first principles. In this review we analyze recent developments high-throughput deep mutational scanning functions; applications latest adaptations Alpha-fold structural prediction methods dynamics allostery; frontiers integrating machine enhanced sampling techniques advances systems. We also highlight SARS-CoV-2 spike (S) revealing an important often hidden role regulation driving functional changes, binding interactions with host receptor, escape S which critical viral infection. conclude a summary outlook future directions suggesting that AI-augmented biophysical computer simulation beginning transform toward systematic landscapes, may bring about revolution drug discovery.

Language: Английский

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AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Journal Year: 2024, Volume and Issue: 16(9), P. 1458 - 1458

Published: Sept. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

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Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 249 - 249

Published: Feb. 8, 2025

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff between multiple energetic factors interaction contributions evolving escape hotspots involved in antigenic drift convergent evolution. However, dynamic details quantifying contribution these factors, particularly balancing nature specific interactions formed antibodies with epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing antibodies: E1 group (BD55-3152, BD55-3546, BD5-5840) F3 (BD55-3372, BD55-4637, BD55-5514). Using approaches, examined determinants which potent can evade immune resistance. Our analysis revealed emergence a small number positions correspond to R346 K444 strong van der Waals act synchronously, leading large contribution. According our results, Abs effectively exploit hotspot clusters hydrophobic sites are critical functions along selective complementary targeting positively charged important ACE2 binding. Together conserved epitopes, lead expand breadth resilience neutralization shifts associated viral The results study demonstrate excellent qualitative agreement predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Language: Английский

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Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1143 - 1143

Published: May 10, 2023

Evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity for ACE2, conformational plasticity, protein stability allosteric modulation. In this study, we systematically characterize dynamics, structural affinities SARS-CoV-2 Spike complexes with host receptor ACE2 BA.2, BA.2.75, XBB.1 XBB.1.5 variants. We combined multiscale molecular simulations dynamic analysis interactions together ensemble-based mutational scanning residues network modeling epistatic interactions. This multifaceted computational study characterized mechanisms identified energetic hotspots mediate predicted increased enhanced BA.2.75 complexes. The results a mechanism driven spatially localized group centers, while allowing functionally beneficial neutral mutations in other interface positions. A network-based community model contributions is proposed revealing key role R498 Y501 mediating community-based couplings sites compensatory dynamics changes. also showed convergent evolutionary hotspot F486 modulate not only local but rewire global communities region F486P mutation to restore both variant which may explain growth advantages over variant. are consistent broad range rationalizing roles form coordinated enabling balance tradeoffs shaping up complex landscape virus transmissibility.

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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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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 3, 2024

Abstract In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles binding mechanisms convergent evolution the SARS-CoV-2 Spike Omicron variants BA.1, BA.2, BA.2.75, BA.3, BA.4/BA.5 BQ.1.1. We employed validated several different adaptations AlphaFold methodology including introduced randomized full sequence scanning manipulation variations systematically explore dynamics complexes with ACE2 receptor. Microsecond dynamic provide a detailed characterization landscapes thermodynamic stability variant complexes. By integrating predictions from applying statistical confidence metrics can expand identify functional conformations that determine equilibrium ACE2. Conformational RBD-ACE2 obtained using are accurate comparative prediction energetics revealing an excellent agreement experimental data. particular, results demonstrated AlphaFold-generated extended produce energies The study suggested complementarities potential synergies between showing information both methods potentially yield more adequate This provides insights in interplay binding, through acquisition mutational sites may leverage adaptability couplings key energy hotspots optimize affinity enable immune evasion.

Language: Английский

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AlphaFold2 Predictions of Conformational Ensembles and Atomistic Simulations of the SARS-CoV-2 Spike XBB Lineages Reveal Epistatic Couplings between Convergent Mutational Hotspots that Control ACE2 Affinity

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(19), P. 4696 - 4715

Published: May 2, 2024

In this study, we combined AlphaFold-based atomistic structural modeling, microsecond molecular simulations, mutational profiling, and network analysis to characterize binding mechanisms of the SARS-CoV-2 spike protein with host receptor ACE2 for a series Omicron XBB variants including XBB.1.5, XBB.1.5+L455F, XBB.1.5+F456L, XBB.1.5+L455F+F456L. dynamic modeling Spike lineages can accurately predict experimental structures conformational ensembles complexes ACE2. Microsecond dynamics simulations identified important differences in landscapes equilibrium variants, suggesting that combining AlphaFold predictions multiple conformations provide complementary approach characterization functional states mechanisms. Using ensemble-based profiling residues physics-based rigorous calculations affinities, energy hotspots characterized basis underlying epistatic couplings between convergent hotspots. Consistent experiments, results revealed mediating role Q493 hotspot synchronization L455F F456L mutations, providing quantitative insight into energetic determinants lineages. We also proposed network-based perturbation allosteric communications uncovered relationships centers long-range communication couplings. The study support mechanism which may be determined by effects evolutionary control binding.

Language: Английский

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Atomistic Prediction of Structures, Conformational Ensembles and Binding Energetics for the SARS-CoV-2 Spike JN.1, KP.2 and KP.3 Variants Using AlphaFold2 and Molecular Dynamics Simulations: Mutational Profiling and Binding Free Energy Analysis Reveal Epistatic Hotspots of the ACE2 Affinity and Immune Escape

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Abstract The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles Spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning spike protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions enable protect restore affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class-1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

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Mutational Scanning and Binding Free Energy Computations of the SARS-CoV-2 Spike Complexes with Distinct Groups of Neutralizing Antibodies: Energetic Drivers of Convergent Evolution of Binding Affinity and Immune Escape Hotspots

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1507 - 1507

Published: Feb. 11, 2025

The rapid evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural energetic analysis spike receptor-binding domain (RBD) complexes neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, B AZD8895 REGN10933, C LY-CoV555, D AZD1061, REGN10987, LY-CoV1404. Using coarse-grained simplified simulation models, energy-based mutational scanning, rigorous MM-GBSA binding free energy calculations, elucidated molecular mechanisms antibody escape mechanisms, identified key hotspots, explored evolutionary strategies employed by virus evade neutralization. residue-based decomposition revealed thermodynamic factors underlying effect mutations on binding. results demonstrate excellent qualitative agreement between predicted hotspots latest experiments escape. These findings provide valuable insights into determinants viral escape, highlighting importance targeting conserved epitopes leveraging combination therapies mitigate risk evasion.

Language: Английский

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