Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113444 - 113444

Published: Nov. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Language: Английский

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Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4281 - 4281

Published: April 12, 2024

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with host cell receptor ACE2 and panel diverse class one antibodies. The central objective investigation was to examine molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing antibody evasion variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.5 + L455F/F456L. By combining evolutionary analysis, dynamics simulations, ensemble-based mutational scanning protein residues in complexes ACE2, identified structural stability affinity are consistent results biochemical studies. agreement deep experiments, our quantitative analysis correctly reproduced strong variant-specific effects BA.2 variants. It shown Y453W F456L mutations can enhance when coupled Q493 while these become destabilized R493 position variant. provided rationale mechanism variants, showing role Q493/R493 hotspot modulating between sites L455F lineages. receptors antibodies provide experimental evidence interactions physically proximal Y501, R498, Q493, L455F, determine binding, F486P instrumental mediating broad resistance. supports which impact on is mediated through small group universal hotspots, effect immune could be more variant-dependent modulated by conformationally adaptable regions.

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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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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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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Structural Changes at the Zinc Active Site of ACE2 on Binding the SARS-CoV-2 Spike Protein Receptor Binding Domain

Inorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

The causative agent of Covid-19 is the SARS-CoV-2 virus. Initiation cell entry by critically dependent upon binding spike protein to angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23). mechanism receptor domain ACE2 among most intensively studied infection mechanisms any pathogen, including a very large number structural studies. membrane-associated zinc carboxypeptidase, comprising three domains, protease domain, neck and membrane-spanning α-helical domain. In addition its role as also chaperone for Na+–amino acid cotransporter called B0AT1, in presence full-length forms dimers. Most studies date related have employed just neglected possible roles Zn2+-containing active site. We show here that ACE2, (and absence B0AT1), dimeric shows distinctive allostery catalytic activity. contrast, monomeric no allostery. Binding (RBD) eliminates X-ray absorption spectroscopy Zn2+ changes site structure RBD but only form. Taken together, our results indicate exhibits notable level flexibility form both likely presents superior model study ACE2-spike interactions than ACE2.

Language: Английский

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SARS-related coronavirus S-protein structures reveal synergistic RBM interactions underpinning high-affinity human ACE2 binding

Science Advances, Journal Year: 2025, Volume and Issue: 11(11)

Published: March 14, 2025

High-affinity and specific binding toward the human angiotensin-converting enzyme 2 (hACE2) receptor by severe acute respiratory syndrome coronavirus (SARS)–related coronaviruses (SARSr-CoVs) remains incompletely understood. We report cryo–electron microscopy structures of eight different S-proteins from SARSr-CoVs found across Asia, Europe, Africa. These all adopt tightly packed, locked, prefusion conformations. enable classification SARSr-CoV into three types, based on their receptor-binding motif (RBM) ACE2 characteristics. Type-2 often preferentially bind bat (bACE2) over hACE2. a structure type-2 BtKY72-RBD in complex with bACE2 to understand specificity. Structure-guided mutagenesis reveals that multiple synergistic mutations four regions RBM are required achieve high-affinity hACE2 binding. Similar changes can also confer another BM48-31 S-protein, which is primarily non-ACE2 results provide an understanding how may be acquired S-proteins.

Language: Английский

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Structural basis for raccoon dog receptor recognition by SARS-CoV-2

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(5), P. e1012204 - e1012204

Published: May 6, 2024

Since the COVID-19 outbreak, raccoon dogs have been suggested as a potential intermediary in transmitting SARS-CoV-2 to humans. To understand their role pandemic and species barrier for transmission humans, we analyzed how ACE2 protein interacts with spike protein. Biochemical data showed that dog is an effective receptor protein, though not human ACE2. Structural comparisons highlighted differences virus-binding residues of compared (L24Q, Y34H, E38D, T82M, R353K), explaining varied effectiveness receptors SARS-CoV-2. These variations contribute exists between humans regarding transmission. Identifying these barriers can help assess susceptibility other mammals Our research underscores carriers identifies molecular affect virus’s ability jump species.

Language: Английский

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Assessing the Potential Contribution of in Silico Studies in Discovering Drug Candidates that Interact with Various SARS-CoV-2 Receptors

Published: Aug. 4, 2023

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly search candidates that interact with various SARS-CoV-2 receptors. These involve use of computer simulations and computational algorithms predict potential interaction target The primary receptors targeted by include RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, AP2-associated protein kinase 1. identified several promising candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, Camostat mesylate, among others. offers advantages, ability screen large number relatively short amount time, thereby reducing time cost involved traditional methods. Additionally, allow prediction binding affinity receptors, providing insight into their efficacy. However, it is crucial consider both advantages limitations these complement them experimental validation ensure efficacy safety candidates.

Language: Английский

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Divergent pathogenetic outcomes in BALB/c mice following Omicron subvariant infection

Virus Research, Journal Year: 2024, Volume and Issue: 341, P. 199319 - 199319

Published: Jan. 21, 2024

Following the emergence of B.1.1.529 Omicron, SARS-CoV-2 virus evolved into a significant number sublineage variants that possessed numerous mutations throughout genome, but particularly within spike glycoprotein (S) gene. For example, BQ.1.1 and XBB.1 XBB.1.5 subvariants contained 34 41 in S, respectively. However, these elicited largely replication only or mild disease phenotypes mice. To better model pathogenic outcomes measure countermeasure performance, we developed mouse adapted versions (BQ.1.1 MA; MA) reflect more acute phase pulmonary symptoms SARS-CoV-2, as well derivative strains expressing nano-luciferase (nLuc) place ORF7 nLuc; nLuc). Amongst (MA) viruses, wide range were observed including mortality, weight loss, lung dysfunction, tissue viral loads nasal turbinates. Intriguingly, MA strains, which identical except at position F486S/P exhibited divergent mice (Ao et al., 2023). infection was associated with loss ∼45 % mortality across two independent studies, while infected animals suffered from 10 same studies. Additionally, development use nanoluciferase provided moderate throughput for live neutralization assays. The availability small animal models assessment Omicron VOC potential will enable refined capacity to evaluate efficacy on market pre-clinical therapeutics interventions.

Language: Английский

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