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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Allosteric Control of Structural Mimicry and Mutational Escape in the SARS-CoV-2 Spike Protein Complexes with the ACE2 Decoys and Miniprotein Inhibitors: A Network-Based Approach for Mutational Profiling of Binding and Signaling

Journal of Chemical Information and Modeling, Journal Year: 2021, Volume and Issue: 61(10), P. 5172 - 5191

Published: Sept. 22, 2021

We developed a computational framework for comprehensive and rapid mutational scanning of binding energetics residue interaction networks in the SARS-CoV-2 spike protein complexes. Using this approach, we integrated atomistic simulations conformational landscaping complexes with ensemble-based screening network modeling to characterize mechanisms structure–functional mimicry resilience toward escape by ACE2 decoy de novo designed miniprotein inhibitors. A detailed analysis structural plasticity proteins obtained from landscapes sequence-based profiling disorder propensities revealed intrinsically flexible regions that harbor key functional sites targeted circulating variants. The conservation collective dynamics showed positions are important modulation motions changes these can alter allosteric networks. Through complexes, identified regulatory hotspots collectively determine response miniproteins results suggest affinities signatures be determined dynamic crosstalk between structurally stable centers conformationally adaptable control escape. This may underlie mechanism which moderate perturbations induce global modulating signaling

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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Exploring Conformational Landscapes and Binding Mechanisms of Convergent Evolution for the SARS-CoV-2 Spike Omicron Variant Complexes with the ACE2 Receptor Using AlphaFold2-Based Structural Ensembles and Molecular Dynamics Simulations

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(25), P. 17720 - 17744

Published: Jan. 1, 2024

In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles evolution binding mechanisms convergent 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 (MD) 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 MD 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 dynamic couplings key energy hotspots optimize affinity enable immune evasion.

Language: Английский

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Using residue interaction networks to understand protein function and evolution and to engineer new proteins

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 89, P. 102922 - 102922

Published: Sept. 26, 2024

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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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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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

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4955 - 4955

Published: May 1, 2024

Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite increasing interest and effort in discovering inhibitors viral activity interactions with host receptor ACE2. The challenges modulators proteins are associated diversity cryptic sites complex molecular that can be employed by ligands, including alteration conformational equilibrium protein preferential stabilization specific functional states. In current study, we combine dynamics analysis distinct forms full-length trimers machine-learning-based binding pocket detection ensemble-based ligand docking free energy to characterize potential determine structural energetic determinants inhibition a series experimentally validated molecules. results demonstrate good agreement between computational experimental affinities, providing support predicted modes suggesting key formed ligands elicit observed inhibition. We establish known molecules, indicating mechanism modulation targeting hinges inter-protomer movements blocking changes closed open trimer forms. this study combining states rigorous enables robust characterization modes, identification hotspots, prediction affinities modulators, which is consistent data. This suggested adaptability bound conformations both play enable efficient interfere changes.

Language: Английский

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Allosteric antibodies: a novel paradigm in drug discovery

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Allostery represents a fundamental mechanism in protein regulation, enabling modulation of function from sites distal to the active site. While traditionally explored context small molecules, allosteric is gaining traction as main mode action realm antibodies, which offer enhanced specificity and reduced toxicity. This review delves into rapidly growing field highlighting recent therapeutic advancements novel druggability avenues. We also explore potential these antibodies innovative tools drug discovery discuss contemporary strategies for designing leveraging state-of-the-art computational approaches.

Language: Английский

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