AlphaFold2 Modeling and Molecular Dynamics Simulations of the Conformational Ensembles for the SARS-CoV-2 Spike Omicron JN.1, KP.2 and KP.3 Variants: Mutational Profiling of Binding Energetics Reveals Epistatic Drivers of the ACE2 Affinity and Escape Hotspots of Antibody Resistance

Viruses, Journal Year: 2024, Volume and Issue: 16(9), P. 1458 - 1458

Published: Sept. 13, 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth fitness due to convergent evolution functional hotspots. These hotspots operate in tandem optimize both receptor binding for effective infection immune evasion efficiency, thereby maintaining overall fitness. lack molecular details on structure, dynamics energetics the latest FLiRT FLuQE with ACE2 antibodies provides a considerable challenge that is explored this study. We combined AlphaFold2-based atomistic predictions structures conformational ensembles spike complexes host dominant JN.1, KP.1, KP.2 KP.3 examine mechanisms underlying role balancing antibody evasion. Using ensemble-based mutational scanning protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions protect restore ACE2-binding affinity while conferring beneficial escape. To escape mechanisms, performed structure-based profiling several classes displayed impaired neutralization against BA.2.86, KP.3. confirmed experimental data harboring L455S F456L mutations can significantly impair neutralizing activity class 1 monoclonal antibodies, effects mediated by facilitate subsequent convergence Q493E changes rescue binding. Structural energetic analysis provided rationale showing BD55-5840 BD55-5514 bind different epitopes retain efficacy all examined support notion may favor emergence lineages combinations involving mediators control balance high

Language: Английский

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Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 4, 2024

Abstract The recent emergence of SARS-CoV-2 variants KP.2 and KP.3 has been marked by mutations F456L/R346T F456L/Q493E, respectively, which significantly impact the virus’s interaction with human ACE2 its resistance to neutralizing antibodies. KP.3, featuring F456L Q493E, exhibits a markedly enhanced binding affinity compared JN.1 variant due synergistic effects between these mutations. This study elucidated structures RBD in complex using cryogenic electron microscopy (Cryo-EM) decipher structural thermodynamic implications on receptor molecular dynamics (MD) simulations, revealing that mutation facilitates more favorable environment for leading stronger interactions consequently enhance potential incorporating additional evasive These results underscore importance understanding mutational epistatic predicting evolution optimizing vaccine updates. Continued monitoring such is crucial anticipating new dominant strains preparing appropriate public health responses.

Language: Английский

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mRNA vaccines with RBD mutations have broad-spectrum activity against SARS-CoV-2 variants in mice

npj Vaccines, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 13, 2025

The emergence of SARS-CoV-2 variants with defined mutations that enhance pathogenicity or facilitate immune evasion has resulted in a continual decline the protective efficacy existing vaccines. Therefore, there is pressing need for vaccine capable combating future variants. In this study, we designed new mRNA vaccines, BSCoV05 and BSCoV06, generated point receptor-binding domain (RBD) original Wuhan strain to increase their broad-spectrum antiviral activity. Additionally, used BA.1 RBD as control. Both vaccines elicited robust response BALB/c K18-hACE2 mice, generating high levels specific binding antibodies against BA.2 RBD. Moreover, all three induced neutralizing prototype viral relevant variants, including Alpha Beta strains Omicron BA.1, BA.2, BA.5, XBB.1.5, XBB.1.16, EG.5.1, EG.5.1.1, BSCoV06 demonstrating broader antibody also cellular response. After challenge, both BSCOV06 provided protection EG.5.1 mouse strains. these two merit further evaluation nonhuman primates, design strategy should be explored its potential application offering valuable insights into development.

Language: Английский

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A Structural Voyage Toward the Landscape of Humoral and Cellular Immune Escapes of SARS‐CoV‐2

Immunological Reviews, Journal Year: 2025, Volume and Issue: 330(1)

Published: Feb. 5, 2025

ABSTRACT The genome‐based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in the past nearly 5 years since its emergence has refreshed our understanding virus evolution, especially on convergent co‐evolution with host. SARS‐CoV‐2 evolution been characterized by sets mutations that affect functional properties altering infectivity, virulence, transmissibility, and interactions host immunity. This poses a huge challenge to global prevention control measures based drug treatment vaccine application. As one key evasion strategies response immune profile human population, there are overwhelming amounts evidence for reduced antibody neutralization variants. Additionally, data also suggest levels CD4 + CD8 T‐cell responses against variants or sub‐variants decrease populations, although non‐negligible cross‐T‐cell maintained. Herein, from perspectives structural immunology, we outline characteristics mechanisms T cell SARS‐CoV variants/sub‐variants. molecular bases impact escaping interaction epitopes receptors adaptive immunity, is, major histocompatibility complex (MHC), receptor (TCR), summarized discussed, knowledge which will widen this pandemic‐threatening assist preparedness Pathogen X future.

Language: Английский

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Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 249 - 249

Published: Feb. 8, 2025

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff between multiple energetic factors interaction contributions evolving escape hotspots involved in antigenic drift convergent evolution. However, dynamic details quantifying contribution these factors, particularly balancing nature specific interactions formed antibodies with epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing antibodies: E1 group (BD55-3152, BD55-3546, BD5-5840) F3 (BD55-3372, BD55-4637, BD55-5514). Using approaches, examined determinants which potent can evade immune resistance. Our analysis revealed emergence a small number positions correspond to R346 K444 strong van der Waals act synchronously, leading large contribution. According our results, Abs effectively exploit hotspot clusters hydrophobic sites are critical functions along selective complementary targeting positively charged important ACE2 binding. Together conserved epitopes, lead expand breadth resilience neutralization shifts associated viral The results study demonstrate excellent qualitative agreement predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Language: Английский

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Mutational Scanning and Binding Free Energy Computations of the SARS-CoV-2 Spike Complexes with Distinct Groups of Neutralizing Antibodies: Energetic Drivers of Convergent Evolution of Binding Affinity and Immune Escape Hotspots

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1507 - 1507

Published: Feb. 11, 2025

The rapid evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural energetic analysis spike receptor-binding domain (RBD) complexes neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, B AZD8895 REGN10933, C LY-CoV555, D AZD1061, REGN10987, LY-CoV1404. Using coarse-grained simplified simulation models, energy-based mutational scanning, rigorous MM-GBSA binding free energy calculations, elucidated molecular mechanisms antibody escape mechanisms, identified key hotspots, explored evolutionary strategies employed by virus evade neutralization. residue-based decomposition revealed thermodynamic factors underlying effect mutations on binding. results demonstrate excellent qualitative agreement between predicted hotspots latest experiments escape. These findings provide valuable insights into determinants viral escape, highlighting importance targeting conserved epitopes leveraging combination therapies mitigate risk evasion.

Language: Английский

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Epimaps of the SARS-CoV-2 Receptor-Binding Domain Mutational Landscape: Insights into Protein Stability, Epitope Prediction, and Antibody Binding

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 301 - 301

Published: Feb. 18, 2025

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses an ongoing threat to the efficacy vaccines and therapeutic antibodies. Mutations predominantly affect receptor-binding domain (RBD) spike protein, which mediates viral entry. RBD is also a major target monoclonal antibodies that were authorised for use during pandemic. In this study, in silico approach was used investigate mutational landscape SARS-CoV-2 variants, including currently circulating Omicron subvariants. A total 40 single-point mutations assessed their potential effect on protein stability dynamics. Destabilising effects predicted such as L455S F456L, while stabilising R346T. Conformational B-cell epitope predictions subsequently performed wild-type (WT) variant RBDs. from located within residues regions found correspond sites targeted by Furthermore, homology models generated utilised protein-antibody docking. binding characteristics 10 against WT 14 evaluated. Through evaluating affinities, interactions, energy contributions residues, contributing evasion identified. findings study provide insight into structural molecular mechanisms underlying neutralising antibody evasion. Future development could focus broadly antibodies, engineering with enhanced affinity, targeting beyond RBD.

Language: Английский

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The Omicron variant BA.2.86.1 of SARS- CoV-2 demonstrates an altered interaction network and dynamic features to enhance the interaction with the hACE2

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 22, 2025

Language: Английский

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Recent SARS-CoV-2 evolution trajectories indicate the emergence of Omicron’s several subvariants and the current rise of KP.3.1.1 and XEC

Virology, Journal Year: 2025, Volume and Issue: unknown, P. 110508 - 110508

Published: March 1, 2025

Language: Английский

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Regional Dynamics and Mechanisms Behind SARS-CoV-2 XDV.1 Prevalence in Chongqing via Genomic Surveillance and Molecular Insights

Virus Research, Journal Year: 2025, Volume and Issue: unknown, P. 199562 - 199562

Published: March 1, 2025

Language: Английский

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