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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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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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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Probing conformational landscapes of binding and allostery in the SARS-CoV-2 omicron variant complexes using microsecond atomistic simulations and perturbation-based profiling approaches: hidden role of omicron mutations as modulators of allosteric signaling and epistatic relationships

Physical Chemistry Chemical Physics, Journal Year: 2023, Volume and Issue: 25(32), P. 21245 - 21266

Published: Jan. 1, 2023

In this study, we systematically examine the conformational dynamics, binding and allosteric communications in Omicron BA.1, BA.2, BA.3 BA.4/BA.5 spike protein complexes with ACE2 host receptor using molecular dynamics simulations perturbation-based network profiling approaches. Microsecond atomistic provided a detailed characterization of landscapes revealed increased thermodynamic stabilization BA.2 variant which can be contrasted variants inducing significant mobility complexes. Using dynamics-based mutational scanning residues, identified structural stability affinity hotspots Perturbation response network-based approaches probed effect mutations on interactions The results analysis specific roles as conformationally plastic evolutionary adaptable modulators allostery are coupled to major regulatory positions through interaction networks. Through perturbation residue potentials performed background original strain, characterized regions epistatic couplings that centered around N501Y Q498R. Our dissected vital role these centers regulating stability, efficient allows for accumulation multiple immune escape at other sites. integrative computational approaches, study provides systematic effects thermodynamics, signaling receptor.

Language: Английский

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Probing Mechanisms of Binding and Allostery in the SARS-CoV-2 Spike Omicron Variant Complexes with the Host Receptor: Revealing Functional Roles of the Binding Hotspots in Mediating Epistatic Effects and Communication with Allosteric Pockets

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11542 - 11542

Published: Sept. 29, 2022

In this study, we performed all-atom MD simulations of RBD-ACE2 complexes for BA.1, BA.1.1, BA.2, and BA.3 Omicron subvariants, conducted a systematic mutational scanning the binding interfaces analysis electrostatic effects. The free energy computations comprehensive examination interactions quantify driving forces provide new insights into energetic mechanisms underlying evolutionary differences between variants. A RBD residues determines protein stability centers hotpots in complexes. By employing ensemble-based global network analysis, propose community-based topological model that characterized functional roles sites mediating non-additive epistatic effects mutations. Our findings suggest contributions to affinity may be mediated by R493, Y498, Y501 are greater BA.1.1 BA.2 display strongest ACE2 among subvariants. network-centric adaptation reversed allosteric communication is unveiled which established robust connection hotspots potential pockets. Using approach, demonstrated long-range could anchor experimentally validated Through an array complementary approaches proposed models, multi-faceted computational study revealed quantified multiple key site R498, acting as hotspots, drivers well mediators communications with

Language: Английский

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Machine learning and protein allostery

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 48(4), P. 375 - 390

Published: Dec. 21, 2022

Language: Английский

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AlphaFold2-Enabled Atomistic Modeling of Structure, Conformational Ensembles, and Binding Energetics of the SARS-CoV-2 Omicron BA.2.86 Spike Protein with ACE2 Host Receptor and Antibodies: Compensatory Functional Effects of Binding Hotspots in Modulating Mechanisms of Receptor Binding and Immune Escape

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(5), P. 1657 - 1681

Published: Feb. 19, 2024

The latest wave of SARS-CoV-2 Omicron variants displayed a growth advantage and increased viral fitness through convergent evolution functional hotspots that work synchronously to balance requirements for productive receptor binding efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with atomistic simulations mutational profiling energetics stability prediction comprehensive analysis the structure, dynamics, BA.2.86 spike variant ACE2 host distinct classes antibodies. We adapted several AlphaFold2 predict both structure conformational ensembles protein in complex receptor. results showed AlphaFold2-predicted ensemble can accurately capture main states variant. Complementary predictions, microsecond molecular dynamics reveal details landscape produced equilibrium structures are used perform scanning residues characterize energy hotspots. ensemble-based domain BA.2 complexes revealed group conserved hydrophobic critical variant-specific contributions R403K, F486P, R493Q. To examine evasion properties detail, performed structure-based interfaces antibodies significantly reduced neutralization against basis compensatory effects hotspots, showing lineage may have evolved outcompete other subvariants by improving while preserving affinity via effect R493Q F486P This study demonstrated an integrative approach combining predictions complementary robust enable accurate characterization mechanisms newly emerging variants.

Language: Английский

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Computer Simulations and Network-Based Profiling of Binding and Allosteric Interactions of SARS-CoV-2 Spike Variant Complexes and the Host Receptor: Dissecting the Mechanistic Effects of the Delta and Omicron Mutations

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4376 - 4376

Published: April 15, 2022

In this study, we combine all-atom MD simulations and comprehensive mutational scanning of S-RBD complexes with the angiotensin-converting enzyme 2 (ACE2) host receptor in native form as well Delta Omicron variants to (a) examine differences dynamic signatures (b) identify critical binding hotspots sensitivity positions. We also examined allosteric interactions communications for variants. Through perturbation-based propensities SARS-CoV-2 residues dynamics-based network centrality community analyses, characterize global mediating centers nature local stabilizing communities. show that a constellation sites (G496S, Q498R, N501Y Y505H) correspond key energy contribute decisively interfacial communities mediate between ACE2. These mutations are responsible both favorable long-range interactions, providing functional high transmissibility virus. At same time, our results other could provide “flexible shield” surrounding stable network, thereby allowing virus modulate immune evasion at different epitopes, while protecting integrity RBD–ACE2 complexes. This study suggests S protein may exploit plasticity RBD generate escape mutants, engaging small group efficient

Language: Английский

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Structural and Computational Studies of the SARS-CoV-2 Spike Protein Binding Mechanisms with Nanobodies: From Structure and Dynamics to Avidity-Driven Nanobody Engineering

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(6), P. 2928 - 2928

Published: March 8, 2022

Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, solubility, the ability to be bioengineered into novel multivalent, multi-specific, high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on design, protein engineering, structure-functional characterization nanobodies binding with SARS-CoV-2 S proteins reflected growing realization that nanobody combinations can exploit distinct epitopes leverage intrinsic plasticity conformational landscape for produce efficient neutralizing mutation resistant characteristics. Structural computational studies have also been instrumental in quantifying structure, dynamics, energetics spike nanobodies. In this review, comprehensive analysis current structural, biophysical, biology investigations complexes classes targeting different sites is presented. The supplemented by an in-depth examination mutational scanning simulations identification energy hotspots classes. review focused mechanisms underlying synergistic multivalent superior single conventional cocktails combating escape mutations effectively leveraging avidity allosteric cooperativity. We discuss how structural insights engineering approaches together tools aid rational design exhibit neutralization characteristics owing avidity-mediated mechanisms.

Language: Английский

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