Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 14, 2023

SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequent membrane fusion. It exists in a range of conformations, including closed state unable to bind the ACE2 receptor, an open that does so but displays more exposed antigenic surface. Spikes variants concern (VOCs) acquired amino acid changes linked increased virulence immune evasion. Here, using HDX-MS, we identified dynamics associate with transition from binding, specific mutations VOCs. We show RBD-associated subdomain plays role opening, whereas NTD acts as hotspot conformational divergence VOC spikes driving Alpha, beta delta assume predominantly conformations increases their core helices, priming for Conversely, substitutions omicron lead presumably enabling it escape antibodies. At same time, its helices characteristics being pre-primed fusion even absence ACE2. These data inform on evolution variant emergence.

Язык: Английский

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Immune imprinting and next-generation coronavirus vaccines

Nature Microbiology, Год журнала: 2023, Номер 8(11), С. 1971 - 1985

Опубликована: Ноя. 6, 2023

Язык: Английский

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Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk with altered NTD dynamics

eLife, Год журнала: 2023, Номер 12

Опубликована: Март 17, 2023

SARS-CoV-2 emergent variants are characterized by increased viral fitness and each shows multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied track changes in S dynamics from variants. Our results highlight large differences across at two loci with impacts on stability. A significant enhancement stabilization first occurred emergence of D614G followed smaller, progressive subsequent Stabilization preceded altered N-terminal domain, wherein Omicron BA.1 showed largest magnitude increases relative other preceding Changes resulting detail evolutionary trajectory emerging These carry major implications for offer new insights into variant-specific therapeutic development.

Язык: Английский

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The Interplay of Furin Cleavage and D614G in Modulating SARS-CoV-2 Spike Protein Dynamics

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Summary We report a detailed analysis of the full-length SARS-CoV-2 spike dynamics within native-like membrane environment and variants inaccessible to studies on soluble constructs by conducting hydrogen-deuterium exchange mass spectrometry (HDX-MS) enveloped virus-like particles (eVLPs) displaying various constructs. find that previously identified open-interface trimer conformation is sampled in all eVLP-displayed studied including sequences from engineered vaccine native viral sequences. The D614G mutation, which arose early pandemic, favors canonical ‘closed-interface’ prefusion conformation, potentially mitigating premature S1 shedding presence cleaved furin site providing an evolutionary advantage virus. Remarkably, cleavage at S1/S2 boundary allosterically increases flexibility S2’ site, may facilitate increased TMPRSS2 processing, enhancing infectivity. use eVLPs HDX-MS provides powerful platform for studying proteins near-native environments.

Язык: 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, Год журнала: 2023, Номер 15(5), С. 1143 - 1143

Опубликована: Май 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.

Язык: 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), 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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hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics

ACS Infectious Diseases, Год журнала: 2023, Номер 9(6), С. 1180 - 1189

Опубликована: Май 11, 2023

SARS-CoV and SARS-CoV-2 cell entry begins when spike glycoprotein (S) docks with the human ACE2 (hACE2) receptor. While two coronaviruses share a common receptor architecture of S, they exhibit differences in interactions hACE2 as well proteolytic processing S that trigger fusion machine. Understanding how those impact activation is key to understand its function viral pathogenesis. Here, we investigate hACE2-induced using hydrogen/deuterium-exchange mass spectrometry (HDX-MS). HDX-MS revealed dynamics unbound including open/closed conformational switching D614G-induced stability. Upon binding, notable transduction allosteric changes were observed extending from binding domain regions proximal cleavage sites peptide. Furthermore, report dimeric hACE2, native oligomeric form receptor, does not lead any more pronounced structural effect compared saturated monomeric binding. These experiments provide mechanistic insights into receptor-induced Sarbecovirus proteins.

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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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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Dynamics, allostery, and stabilities of whole virus particles by amide hydrogen/deuterium exchange mass spectrometry (HDXMS)

Current Opinion in Structural Biology, Год журнала: 2024, Номер 86, С. 102787 - 102787

Опубликована: Март 7, 2024

Язык: Английский

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