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), Год журнала: 2024, Номер unknown

Опубликована: Апрель 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.

Язык: 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), Год журнала: 2024, Номер unknown

Опубликована: Июль 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

Язык: Английский

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Protein–Protein Docking: Past, Present, and Future

The Protein Journal, Год журнала: 2021, Номер 41(1), С. 1 - 26

Опубликована: Ноя. 17, 2021

Язык: 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, Год журнала: 2023, Номер 25(32), С. 21245 - 21266

Опубликована: Янв. 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.

Язык: 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, Год журнала: 2024, Номер 128(19), С. 4696 - 4715

Опубликована: Май 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.

Язык: 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, Год журнала: 2024, Номер 26(25), С. 17720 - 17744

Опубликована: Янв. 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.

Язык: Английский

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Antibody drugs targeting SARS-CoV-2: Time for a rethink?

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 176, С. 116900 - 116900

Опубликована: Июнь 10, 2024

Язык: 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, Год журнала: 2021, Номер 61(10), С. 5172 - 5191

Опубликована: Сен. 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

Язык: Английский

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Intrinsically Disordered Proteins: Perspective on COVID-19 Infection and Drug Discovery

ACS Infectious Diseases, Год журнала: 2022, Номер 8(3), С. 422 - 432

Опубликована: Фев. 23, 2022

Since the beginning of COVID-19 pandemic caused by SARS-CoV-2, millions patients have been diagnosed and many them died from disease worldwide. The identification novel therapeutic targets are utmost significance for prevention treatment COVID-19. SARS-CoV-2 is a single-stranded RNA virus with 30 kb genome packaged into membrane-enveloped virion, transcribing several tens proteins. belief that amino acid sequence proteins determines their 3D structure which, in turn, function has central principle molecular biology long time. Recently, it increasingly realized, however, there large group lack fixed or ordered structure, yet they exhibit important biological activities─so-called intrinsically disordered protein regions (IDPs/IDRs). Disordered viral generally associated infectivity pathogenicity because endow ability to easily promiscuously bind host proteins; therefore, proteome thoroughly examined intrinsic disorder. It recognized that, fact, exhibits significant levels structural order, only nucleocapsid (N) two nonstructural being highly disordered. spike (S) its predicted percentage disorder still higher than SARS-CoV. Noteworthy, even though IDPs/IDRs not common proteome, existing ones play major roles functioning virulence thus promising drug rational antiviral design. Presented here perspective on proteins, summarizing recent results features, physiological pathological relevance, prominence as prospective target sites.

Язык: 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, Год журнала: 2022, Номер 23(19), С. 11542 - 11542

Опубликована: Сен. 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

Язык: Английский

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