Architects of infection: A structural overview of SARS-related coronavirus spike glycoproteins

Virology, Journal Year: 2025, Volume and Issue: unknown, P. 110383 - 110383

Published: Jan. 1, 2025

The frequency of zoonotic viral emergence within the Coronaviridae family highlights critical need to understand structural features spike proteins that govern entry and host adaptation. Investigating conservation variation in key regions protein-those involved range, binding affinity, entry, immune evasion-is essential for predicting evolutionary pathways coronaviruses, assessing risk future host-jumping events, discovering pan-neutralising antibodies. Here we summarise our current understanding similar SARS-CoV-2 from compare functional similarities differences. Our aim is demonstrate significant sequence between a range species outline importance animal coronavirus surveillance investigation endeavour pandemic preparedness against emerging viruses.

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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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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The D614G mutation helps to increase the transmissibility and reduce the virulence of SARS-CoV-2 variants through natural selection

International Journal of Surgery, Journal Year: 2023, Volume and Issue: 109(2), P. 171 - 174

Published: Feb. 1, 2023

The massive surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had significant implications for the population entire world during ongoing disease 2019 (COVID-19) pandemic. SARS-CoV-2 virus, a species family Coronaviridae, is single-stranded RNA virus. Unlike DNA viruses, viruses are prone to mutations. These mutations very rapid and required be part natural selection1. Importantly, evidence suggests that in past decades, spread pandemic was usually altered by such through selection. This selection, followed mutations, reduces virulence which is, turn, beneficial society. same scenario noticeable case virus2. According classifications made WHO Centers Disease Control Prevention, there several emerging variants; some called variants concern, while rest interest. variants, alter types viral characteristics, like transmissibility, vaccine activity, rate infection, etc.3,4. In all these D614G mutation most common found S-protein3. certain data, scientists implied this virus properties. increased fitness transmissibility solely responsible mutation. Due mutation, replication also increases, making more transmissible5. change characteristics raises question when COVID-19 will end. Besides, directly proportional infection. Thus, researchers aim comprehensively analyze genome develop efficient therapeutics eradicate Most importantly, selection always been critical factor regulating evolution various mutants'. Evolution classical acts as driving force select organisms best choice nature. It become prevalent line with theory Charles Darwin's selection2. Scientists have cited positive selection6. not an outcome any ancillary factors genetic drift. significantly, may considered limitation, but drop mortality scientific community's primary concern. Nevertheless, molecular basis should follow where transmission increase, significantly. A detailed understanding help predict diseases' progression upcoming variants. naturally selected observed Alpha, Beta, Delta, Gamma, recent variant, Omicron; one S-protein. present high frequency (Fig. 1). so widespread throughout world. only give extra enhance its capacity transmit mitigate many could deadly. Natural key deciding depending on well-being population. For instance, reducing possible driven somewhat inversely virulence. ideal example it. presence greater extent. However, dropped suggesting potential decrease Omicron variant perfect transmissible least severe7–9. Simultaneously, effective reproductive number(R0) noted 8.2, about 3.8 times superior terms compared Delta variant10,11. concluded helps might reduce along other mutations.Figure 1: phylogenic tree containing frequencies different S-protein (SARS-CoV-2). (a) shows SARS-CoV-2. (b) Mutation show frequency. figure developed COVIDCG GISAID databases.The structural alterations disadvantage interaction specific protein receptor. notable features alters nature generally conformation. evolution, alteration furin cleavage site ACE2 receptor, increasing surface area domain surrounding variation conformational plasticity enlarges volume site, increases host receptor12. spike protein's structure globally result introduction organizes 630-loop structure. contrast disordered structures wild-type protein, organized strength local interactions between 614 residue adjacent residues. creates mobile, asymmetric down conformation speeds up transitions allosterically changing connections receptor-binding regions. often stabilizes proximal region fusion peptide, including protomer. peptide enables membrane causing deletion salt bridge K854 D614 residues13. Moreover, Gellenoncourt et al.14 elucidated generating highly fusogenic spikes emerged due stabilized S1/S2 allowed those capable boosting cleavage. difference interact receptor host. gives additional infecting Out residing domain, interest main reviving among researchers' minds properties became within short period time. By taking closer look at mechanism entry inside cell, it evident glycoprotein plays vital role enhancing virus' receptors cell. order therapeutics, functional landscape complex essential. Several studies highlight given excessive loads predominantly upper parts system15. boon providing fitness. acquired properties, rates As discussed, accelerated paradigm shifts suggest This, depends bottleneck effect, density, lasted environment longer enhanced qualities over other, superiority prevail environment16. evolutionary therapeutics. though they can no neutralize antigens. study helpful community ways. Ethical approval article does require human/animal subjects acquire approval. Sources funding received grant from agency public, commercial, or not-for-profit sectors. Author contribution C.C.: conceived designed analysis, original draft writing. S.C., M.B., H.C., P.B.: M.A.I., K.D.: review editing final version. Conflicts disclosure All authors report conflicts relevant article. Research registration unique identifying number (UIN) Name registry: applicable. Unique ID: Hyperlink your (must publicly accessible checked): Guarantor Md. Aminul Islam, Diagnostic Lab, Department Microbiology, Noakhali Science Technology University, 3814, Bangladesh. E-mail: [email protected] Provenance peer Not commissioned, internally peer-reviewed. Data statement data correspondence sensitive public domain. therefore available confidential No collected above manuscript.

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 22, 2023

Abstract The 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, 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. results a mechanism driven spatially localized group centers, while allowing functionally beneficial neutral mutations in other interface positions. A network-based community model non-additive contributions is proposed revealing key role R498 Y501 mediating community-based couplings sites compensatory dynamics changes. also showed convergent 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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Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers: Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6642 - 6642

Published: April 2, 2023

Evolutionary and functional studies have suggested that the emergence of Omicron variants can be determined by multiple fitness tradeoffs including immune escape, binding affinity, conformational plasticity, protein stability, allosteric modulation. In this study, we embarked on a systematic comparative analysis dynamics, electrostatics, allostery in different states spike trimers for BA.1, BA.2, BA.2.75 variants. Using efficient accurate coarse-grained simulations atomistic reconstruction ensembles, examined dynamics agree with recent studies, suggesting are most stable among these A mutational scanning inter-protomer interfaces revealed group conserved structural stability hotspots play key role modulation also involved couplings through local contacts interaction networks sites. The results provided evidence more than BA.2 comparable to BA.1 variant. dynamic network modeling S trimers, showed mediators interactions associated major interconnected along potential communication pathways. increased thermodynamic variant may linked organization modularity residue allows communications between This study plausible rationale mechanism which mutations evolve targeting vulnerable sites adaptability elicit escape while maintaining their control balancing robust hotspots.

Language: Английский

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Unprecedented spike flexibility revealed by BSL3 Cryo-ET of active SARS-CoV-2 virions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 11, 2023

Abstract Understanding the molecular properties of SARS-CoV-2 is crucial to tackle future outbreaks. Current knowledge trimeric spike protein relies on truncated recombinant proteins and inactivated full-length forms, which may suffer from overstabilization. Here, we apply cryo-electron tomography (cryo-ET) at a Biosafety level 3 facility study virus structure in its native, active state. The particles show variable shapes with diffusible spikes, majority typical prefusion conformations. Notably, also identified unprecedented, atypical open-trimer states, revealing hidden flexibility. sub-tomogram averaged suggests loosely packed trimer. observed dynamics uncover conserved cryptic regions that can be targeted for broadly effective vaccines. Structural analysis viruses will have implications understanding overlooked fusion mechanism vaccine, antibody/drug design. (124 words) One-Sentence Summary BSL3 microscopy uncovered significant flexibility viruses, facilitate design vaccines drugs.

Language: Английский

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Allosteric pathways of SARS and SARS‐CoV‐2 spike protein identified by neural relational inference

Proteins Structure Function and Bioinformatics, Journal Year: 2024, Volume and Issue: 92(7), P. 865 - 873

Published: March 8, 2024

Abstract The receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein must undergo a crucial conformational transition to invade human cells. It is intriguing that this accompanied by synchronized movement the entire protein. Therefore, it possible design allosteric regulators targeting non‐RBD but hindering RBD. To understand mechanism in detail, we establish computational framework integrating coarse‐grained molecular dynamic simulations and state‐of‐the‐art neural network model called relational inference. Leveraging framework, have elucidated pathway SARS‐CoV‐2 at residue level identified mechanisms involved transmission signals. D614 coupled with Q321. This interaction subsequently influences K528/K529, ultimately coupling RBD during changes. Mutations weaken interactions within naturally block signal transmission, thereby modulating transitions. observation also offers rationale for distinct patterns observed SARS‐CoV Our result provides useful method analyzing dynamics potential viral variants future.

Language: Английский

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Intrinsically Disordered Regions Function as a Cervical Collar to Remotely Regulate the Nodding Dynamics of SARS-CoV-2 Prefusion Spike Heads

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(39), P. 8393 - 8405

Published: Sept. 22, 2023

The SARS-CoV-2 prefusion spike heads (receptor binding domains, RBDs) frequently nod down and up to interact with host cell receptors. As the protein is a trimeric unit of significant size, understand its large-scale structural dynamics associated nodding mechanism mutational impact on same, we develop topological symmetry-information-loaded coarse-grained structure-based model trimer using recent cryo-EM data. Our study reveals control two distant intrinsically disordered regions (IDRs), namely, 630 FPPR loops, over heads. We find that order–disorder transition IDRs becomes more evident in variants concern (VOCs) are characteristic mutation, D614G, proximity these IDRs. In some VOCs, other mutations A570D S982A also show an integral effect. driver mutation D614G instigates salt-bridge disruption, altering both loops their interaction C-terminal domains (CTD1/CTD2). This altered connectivity mutants allows act collectively as "cervical collar" for RBD, supporting various head postures, consistent results available specific cases. IDRs' structure presents exciting opportunity where they can be targeted remote operational switches artificially maneuver effective therapeutic interventions.

Language: Английский

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Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 1, 2023

Abstract The evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity, conformational plasticity, protein stability allosteric modulation. In this study, we embarked on a systematic comparative analysis dynamics, electrostatics, allostery in different states spike trimers for BA.1, BA.2, BA.2.75 variants. Using efficient accurate coarse-grained simulations atomistic reconstruction ensembles, examined dynamics agrees with recent studies, suggesting are most stable among these A mutational scanning inter-protomer interfaces revealed group conserved structural hotspots play key role modulation also involved couplings through local contacts interaction networks sites. results provided evidence more than BA.2 comparable to BA.1 variant. dynamic network modeling S showed positions driving long-range signaling associated major inter-connected along potential communication pathways, while sites mutations may often correspond weak spots but coupled networks. presented thermodynamic intimately linked residue organization allows broad ensemble communications which between modulated findings plausible rationale mechanisms evolve balance adaptability order ensure proper tradeoff stability, escape.

Language: Английский

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