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 DOI Open Access
Mohammed Alshahrani, Victoria N. Parikh, Brian Foley

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 20, 2024

Abstract The growing body of experimental and computational studies suggested that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff 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 scarcely characterized. In this study, we performed molecular dynamics simulations, ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing : E1 group (BD55-3152, BD55-3546 BD5-5840) F3 (BD55-3372, BD55-4637 BD55-5514). Using approaches, examine determinants which potent can largely 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 critical functions along selective complementary targeting positively charged are important ACE2 binding. Together conserved epitopes, lead expanded neutralization breadth resilience shift associated viral results study demonstrate excellent qualitative agreement between predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Язык: Английский

Pemivibart is less active against recent SARS-CoV-2 JN.1 sublineages DOI Open Access
Qian Wang, Yicheng Guo,

Jerren Ho

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 13, 2024

Abstract Protection from COVID-19 vaccination is suboptimal in many immunocompromised individuals. In March 2024, the Food and Drug Administration issued an Emergency Use Authorization for pemivibart (Permagard/VYD222), engineered human monoclonal antibody, pre-exposure prophylaxis this vulnerable population. However, SARS-CoV-2 has since evolved extensively, resulting multiple Omicron JN.1 sublineages. We therefore evaluated vitro neutralizing activity of against prevalent forms JN.1, including KP.2, KP.3, KP.2.3, LB.1, and, importantly, KP.3.1.1, which now expanding most rapidly. A panel VSV-based pseudoviruses representing major sublineages was generated to assess their susceptibility neutralization vitro. Structural analyses were then conducted understand impact specific spike mutations on virus-neutralization results. Pemivibart neutralized both KP.2 with comparable activity, whereas its potency decreased slightly KP.3 but substantially KP.3.1.1. Critically, 50% inhibitory concentration KP.3.1.1 ∼6 µg/mL, or ∼32.7 fold higher than that our study. suggest Q493E S31-deletion viral contribute antibody evasion, latter having a more pronounced effect. Our findings show lost substantial rapidly lineage today. Close monitoring clinical efficacy warranted. These results also highlight imperative expand arsenal preventive agents protect millions individuals who could not respond robustly vaccines.

Язык: Английский

Процитировано

7
Atomistic Prediction of Structures, Conformational Ensembles and Binding Energetics for the SARS-CoV-2 Spike JN.1, KP.2 and KP.3 Variants Using AlphaFold2 and Molecular Dynamics Simulations: Mutational Profiling and Binding Free Energy Analysis Reveal Epistatic Hotspots of the ACE2 Affinity and Immune Escape DOI
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 10, 2024

Abstract 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 spike protein residues computations affinities, we identified energy characterized basis epistatic couplings between results suggested existence interactions sites at L455, F456, Q493 positions enable protect restore 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

Язык: Английский

Процитировано

5
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 DOI Creative Commons
Mohammed Alshahrani, Vedant Parikh, Brian Foley

и другие.

Biomolecules, Год журнала: 2025, Номер 15(2), С. 249 - 249

Опубликована: Фев. 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.

Язык: Английский

Процитировано

0
Antibody evasiveness of SARS-CoV-2 subvariants KP.3.1.1 and XEC DOI Creative Commons
Qian Wang, Yicheng Guo, Ian A. Mellis

и другие.

Cell Reports, Год журнала: 2025, Номер 44(4), С. 115543 - 115543

Опубликована: Апрель 1, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and spread, it remains critical understand the functional consequences of mutations in dominant viral variants. The recombinant JN.1 subvariant XEC recently replaced KP.3.1.1 become most prevalent worldwide. Here, we measure vitro neutralization by human sera, monoclonal antibodies, soluble ACE2 (hACE2) receptor relative parental subvariants KP.3 JN.1. are slightly more resistant (1.3- 1.6-fold) than serum antigenically similar. Both also demonstrate greater resistance select antibodies hACE2, all which target top spike. Our findings suggest that upward motion receptor-binding domain spike may be partially hindered N-terminal XEC, allowing these better evade up position have a growth advantage.

Язык: Английский

Процитировано

0
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 DOI
Mohammed Alshahrani, Vedant Parikh, Brian Foley

и другие.

Опубликована: Апрель 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

Язык: Английский

Процитировано

0
Tracking KP.2 SARS-CoV-2 Variant in India and the Clinical Profile of KP.2 Cases in Maharashtra, India DOI Open Access
Rajesh Karyakarte, Rashmita Das, Varsha Potdar

и другие.

Cureus, Год журнала: 2024, Номер unknown

Опубликована: Авг. 3, 2024

Background: Following the emergence of JN.1 SARS-CoV-2 variant, variants with key mutations in spike protein, such as L455F, F456L, and R346T, were identified. In early January 2024, KP.2 (JN.1.11.1.2) variant was first identified clinical samples. Its increasing global prevalence has raised concerns over its transmission impact. The study investigates KP.2*'s (*indicates all sub-lineages) spread severity Maharashtra. Methods: This involved 5,173 Indian whole genome sequences collection dates between November 1, 2023 June 24, 2024. Lineage analysis performed using Nextclade software (version 3.8.0). Telephonic interviews conducted to confirm demographic details obtain information on KP.2* cases. obtained data recorded analyzed Microsoft® Excel (Microsoft Corporation, Redmond, WA). Results: Among analyzed, JN.1* appeared predominant lineage (65.96%, 3412/5173), followed by (7.83%, 405/5173) KP.1* (3.27%, 169/5173). India, detected December 2, 2023, Odisha. majority from Maharashtra (248/405, 61.23%), West Bengal (38/405, 9.38%), Gujarat (27/405, 6.67%), Rajasthan (24/405, 5.93%). reported included 160 cases Of these, 95.63% (153/160) presented mild symptoms, fever (108/160, 67.50%), cold (87/160, 54.38%), cough (80/160, 50%), sore throat (44/160, 27.5%), body ache (43/160, 26.88%), fatigue (42/160, 26.25%). About 33.13% (53/160) required institutional quarantine or hospitalization, rest managed at home. those hospitalized, 50.94% (27/53) received conservative treatment, while 49.06% (26/53) needed supplemental oxygen, steroids, antiviral therapy. Regarding vaccination status, 89.38% (143/160) had least one dose COVID-19 vaccine, whereas 10% (16/160) unvaccinated, unvaccinated being children aged zero nine years (7/16, 43.75%). overall recovery rate for 99.38% (159/160), only 0.62% (1/160) succumbing disease. Conclusion: become dominant India Despite affected individuals experiencing studies have shown lower neutralization titers high infectivity due FLiRT mutations, suggesting KP.2's potential rise dominance.

Язык: Английский

Процитировано

2
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 DOI Open Access
Mohammed Alshahrani, Victoria N. Parikh, Brian Foley

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 20, 2024

Abstract The growing body of experimental and computational studies suggested that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff 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 scarcely characterized. In this study, we performed molecular dynamics simulations, ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing : E1 group (BD55-3152, BD55-3546 BD5-5840) F3 (BD55-3372, BD55-4637 BD55-5514). Using approaches, examine determinants which potent can largely 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 critical functions along selective complementary targeting positively charged are important ACE2 binding. Together conserved epitopes, lead expanded neutralization breadth resilience shift associated viral results study demonstrate excellent qualitative agreement between predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Язык: Английский

Процитировано

0