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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Exploring protein functions from structural flexibility using CABS‐flex modeling

Protein Science, Год журнала: 2024, Номер 33(9)

Опубликована: Авг. 28, 2024

Abstract Understanding protein function often necessitates characterizing the flexibility of structures. However, simulating poses significant challenges due to complex dynamics systems, requiring extensive computational resources and accurate modeling techniques. In response these challenges, CABS‐flex method has been developed as an efficient tool that combines coarse‐grained simulations with all‐atom detail. Available both a web server standalone package, is dedicated wide range users. The version offers accessible interface for straightforward tasks, while command‐line program designed advanced users, providing additional features, analytical tools, support handling large systems. This paper examines application across various structure–function studies, facilitating investigations into interplay among structure, dynamics, in diverse research fields. We present overview current status methodology, highlighting its recent advancements, practical applications, forthcoming challenges.

Язык: 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, Год журнала: 2022, Номер 23(8), С. 4376 - 4376

Опубликована: Апрель 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

Язык: 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, Год журнала: 2024, Номер 64(5), С. 1657 - 1681

Опубликована: Фев. 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.

Язык: 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, Год журнала: 2022, Номер 23(6), С. 2928 - 2928

Опубликована: Март 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.

Язык: Английский

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