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

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 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.

Language: Английский

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Immune imprinting and next-generation coronavirus vaccines

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(11), P. 1971 - 1985

Published: Nov. 6, 2023

Language: 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, Journal Year: 2023, Volume and Issue: 12

Published: March 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.

Language: 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), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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.

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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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), Journal Year: 2024, Volume and Issue: unknown

Published: April 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.

Language: 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, Journal Year: 2023, Volume and Issue: 9(6), P. 1180 - 1189

Published: May 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.

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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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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Variation in structural motifs within SARS-related coronavirus spike proteins

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(5), P. e1012158 - e1012158

Published: May 28, 2024

SARS-CoV-2 is the third known coronavirus (CoV) that has crossed animal-human barrier in last two decades. However, little structural information exists related to close genetic species within SARS-related coronaviruses. Here, we present three novel CoV spike protein structures solved by single particle cryo-electron microscopy analysis derived from bat (bat SL-CoV WIV1) and civet (cCoV-SZ3, cCoV-007) hosts. We report complex glycan trees decorate glycoproteins density for water molecules which facilitated modeling of molecule coordination networks structurally important regions. note conservation fatty acid binding pocket presence a linoleic are associated with stabilization receptor domains “down” conformation. Additionally, N-terminal biliverdin occupied all structures. Finally, analyzed differences loop motif between coronaviruses infect humans animal described this study, regulate human angiotensin converting enzyme 2 receptor. This study offers framework evaluate relatives SARS-CoV-2, ability inform pandemic prevention, aid development pan-neutralizing treatments.

Language: Английский

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