Exploring Diverse Binding Mechanisms of Broadly Neutralizing Antibodies S309, S304, CYFN-1006 and VIR-7229 Targeting SARS-CoV-2 Spike Omicron Variants: Integrative Computational Modeling Reveals Balance of Evolutionary and Dynamic Adaptability in Shaping Molecular Determinants of Immune Escape

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Abstract Evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. The cross-neutralization activity antibodies against Omicron is governed by a complex delicate interplay multiple energetic factors interaction contributions. In this study, we conducted comprehensive analysis interactions between receptor-binding domain (RBD) spike protein four neutralizing S309, S304, CYFN1006, VIR-7229. Using integrative computational modeling that combined all-atom molecular dynamics (MD) simulations, mutational scanning, MM-GBSA binding free energy calculations, elucidated structural, energetic, dynamic determinants antibody binding. Our findings reveal distinct mechanisms evolutionary adaptation driving broad neutralization effect these antibodies. We show S309 targets conserved residues near ACE2 interface, leveraging synergistic van der Waals electrostatic interactions, while S304 focuses on fewer but sensitive residues, making it more susceptible escape mutations. CYFN-1006.1 CYFN-1006.2 highlights epitope coverage critical anchors at T345, K440, T346, enhancing its efficacy carrying K356T mutation which caused from broadly potent VIR-7229 XBB.1.5 EG.5 emphasized large structurally epitope, demonstrating certain adaptability compensatory effects F456L L455S Mutational profiling identified key crucial for binding, including P337, R346 T385 K386 underscoring their roles as "weak spots" balance viral fitness evasion. results demonstrate good agreement predicted hotspots mutations respect latest experiments average scores. study dissect importance targeting diverse epitopes counteract resistance. Broad-spectrum CYFN1006 maintain across achieve convergent evolution enabling tolerance in positions through structural interface. underscore diversity employed different basis high affinity excellent generation

Language: Английский

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Cryo-EM reveals conformational variability in the SARS-CoV-2 spike protein RBD induced by two broadly neutralizing monoclonal antibodies

RSC Advances, Journal Year: 2025, Volume and Issue: 15(18), P. 14385 - 14399

Published: Jan. 1, 2025

Antibody binding to the SARS-CoV-2 spike undergoes intermediate conformational states, revealing dynamic antibody mechanisms.

Language: Английский

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Integrative Computational Modeling of Distinct Binding Mechanisms for Broadly Neutralizing Antibodies Targeting SARS-CoV-2 Spike Omicron Variants: Balance of Evolutionary and Dynamic Adaptability in Shaping Molecular Determinants of Immune Escape

Viruses, Journal Year: 2025, Volume and Issue: 17(6), P. 741 - 741

Published: May 22, 2025

In this study, we conducted a comprehensive analysis of the interactions between receptor-binding domain (RBD) SARS-CoV-2 spike protein and four neutralizing antibodies—S309, S304, CYFN1006, VIR-7229. Using integrative computational modeling that combined all-atom molecular dynamics (MD) simulations, mutational scanning, MM-GBSA binding free energy calculations, elucidated structural, energetic, dynamic determinants antibody binding. Our findings reveal distinct mechanisms evolutionary adaptation driving broad neutralization effect these antibodies. We show S309 targets conserved residues near ACE2 interface, leveraging synergistic van der Waals electrostatic interactions, while S304 focuses on fewer but sensitive residues, making it more susceptible to escape mutations. The CYFN-1006.1 CYFN-1006.2 highlights epitope coverage with critical anchors at T345, K440, T346, enhancing its efficacy against variants carrying K356T mutation, which caused from broadly potent VIR-7229 XBB.1.5 EG.5 Omicron emphasized large structurally complex epitope, demonstrating certain adaptability compensatory effects F456L L455S Mutational profiling identified key crucial for binding, including P337, R346 as well T385 K386 underscoring their roles “weak spots” balance viral fitness immune evasion. results energetic demonstrate good agreement predicted hotspots, highlight importance targeting diverse epitopes counteract resistance.

Language: Английский

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RBD and Spike DNA-Based Immunization in Rabbits Elicited IgG Avidity Maturation and High Neutralizing Antibody Responses against SARS-CoV-2

Viruses, Journal Year: 2023, Volume and Issue: 15(2), P. 555 - 555

Published: Feb. 17, 2023

Neutralizing antibodies (nAbs) are a critical part of coronavirus disease 2019 (COVID-19) research as they used to gain insight into the immune response severe acute respiratory syndrome-related 2 (SARS-CoV-2) infections. Among technologies available for generating nAbs, DNA-based immunization methods an alternative conventional protocols. In this pilot study, we investigated whether by needle injection in rabbits was viable approach produce functional antibody response. We demonstrated that three doses DNA plasmid carrying gene encoding full-length spike protein (S) or receptor binding domain (RBD) SARS-CoV-2 induced time-dependent increase IgG avidity maturation. Moreover, displayed high cross neutralization live and pseudoviruses assays. Thus, established simple, low cost feasible protocol elicited maturation nAbs production against SARS-CoV-2, highlighting importance platforms developing new strategies future emerging epidemics.

Language: Английский

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Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

Viruses, Journal Year: 2023, Volume and Issue: 15(10), P. 2009 - 2009

Published: Sept. 27, 2023

A significant body of experimental structures SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable binding pockets. Understanding interplay conformational dynamics changes induced by Omicron identification cryptic dynamic pockets in S is paramount importance as exploring broad-spectrum antiviral agents to combat emerging imperative. In current study, we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, an allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This study provided structural characterization predicted captured sites, revealing critical role modulating cross-talk between sites. We found that mutational variant can induce remodeling stabilization pocket N-terminal domain, while this drastically altered may no longer be available ligand variant. Our results site receptor-binding domain remains stable ranks most favorable but could become fragmented less probable conformations. also uncovered several formed at inter-domain inter-protomer interface, including regions S2 subunit stem helix region, which are consistent with residues transitions antibody recognition. The particularly understanding features proteins, well effects Omicron-variant-specific modulation preferential exploration present new previously underappreciated opportunity therapeutic interventions through conformation-selective targeting involved changes.

Language: Английский

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