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

et al.

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

Published: Dec. 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.

Language: Английский

Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants DOI Creative Commons

Pei Li,

Julia N. Faraone, Cheng Chih Hsu

et al.

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

Published: Sept. 5, 2024

SUMMARY During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants SARS-CoV-2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2, increased resistance elevated temperatures. Molecular modeling suggests induces conformational change stabilizes strengthens NTD-Receptor-Binding Domain (RBD) interaction, thus favoring down conformation RBD reducing accessibility ACE2 receptor certain nAbs. introduces an N-linked glycan modification at N30, shields underlying region recognition. data highlight critical role mutations for evasion, stability, viral suggest consideration updating vaccines antigens containing DelS31.

Language: Английский

Citations

13
Enhanced immune evasion of SARS-CoV-2 variants KP.3.1.1 and XEC through N-terminal domain mutations DOI
Jingyi Liu, Yuanling Yu, Fanchong Jian

et al.

The Lancet Infectious Diseases, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

12
Activity of Research-Grade Pemivibart against Recent SARS-CoV-2 JN.1 Sublineages DOI Open Access
Qian Wang, Yicheng Guo,

Jerren Ho

et al.

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 391(19), P. 1863 - 1864

Published: Nov. 13, 2024

Language: Английский

Citations

11
A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification DOI Creative Commons
Laura E. Rosen, M. Alejandra Tortorici, Anna De Marco

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing sufficiently potent clinical development and retain activity despite remain elusive. We identified human mAb, designated VIR-7229, which targets the receptor-binding motif (RBM) with unprecedented cross-reactivity all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently SARS-CoV-2 variants since 2019, recent EG.5, BA.2.86, JN.1. VIR-7229 tolerates extraordinary variability, partly attributed its high binding affinity, receptor molecular mimicry, interactions RBM backbone atoms. Consequently, features barrier selection of mutants, rare associated reduced fitness, underscoring potential be future evolution. is strong candidate become next-generation medicine.

Language: Английский

Citations

8
Structural and molecular basis of the epistasis effect in enhanced affinity between SARS-CoV-2 KP.3 and ACE2 DOI Creative Commons
Leilei Feng, Zhaoxi Sun, Yuchen Zhang

et al.

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Nov. 30, 2024

Language: Английский

Citations

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

et al.

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

Citations

0
Increased preference for lysine over arginine in spike proteins of SARS-CoV-2 BA.2.86 variant and its daughter lineages DOI Creative Commons
Anže Božič, Rudolf Podgornik

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(4), P. e0320891 - e0320891

Published: April 7, 2025

The COVID-19 pandemic offered an unprecedented glimpse into the evolution of its causative virus, SARS-CoV-2. It has been estimated that since outbreak in late 2019, virus explored all possible alternatives terms missense mutations for sites polypeptide chain. Spike protein exhibits largest sequence variation particular, with many individual impacting target recognition, cellular entry, and endosomal escape virus. Moreover, recent studies unveiled a significant increase total charge on spike during initial period pandemic. While this trend recently come to halt, we perform sequence-based analysis 2665 SARS-CoV-2 variants which shows ionizable amino acids continue occur newly emerging variants, notable differences between lineages from different clades. What is more, show within can acquire positive charge, prominent preference lysine residues over arginine residues. This lysine-to-arginine ratio increased at several points evolution, most BA.2.86 sublineages, including dominant JN.1, KP.3, XEC variants. consequence structural regions now among highest viral species Coronaviridae family. impact high proteins daughter fitness remains unclear; discuss potential mechanisms could play role serve as starting point further studies.

Language: Английский

Citations

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

et al.

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

Citations

0
Deep mutational scanning and CRISPR-engineered viruses: tools for evolutionary and functional genomics studies DOI Creative Commons
Mercedes Paz, Gonzalo Moratorio

mSphere, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

ABSTRACT Recent advancements in synthetic biology and sequencing technologies have revolutionized the ability to manipulate viral genomes with unparalleled precision. This review focuses on two powerful methodologies: deep mutational scanning CRISPR-based genome editing, that enable comprehensive mutagenesis detailed functional characterization of proteins. These approaches significantly deepened our understanding molecular determinants driving evolution adaptation. Furthermore, we discuss how these advances provide transformative insights for future vaccine development therapeutic strategies.

Language: Английский

Citations

0
Structural Immunology of SARS‐CoV‐2 DOI Creative Commons
Meng Yuan, Ian A. Wilson

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 27, 2024

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, escape mechanisms. Antibodies receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in variants. contrast, conserved regions, such as S2 stem helix fusion peptide, broader reactivity generally lower potency. However, several broadly have demonstrated exceptional efficacy against emerging variants, including latest omicron subvariants, underscoring potential vulnerable sites RBS-A RBS-D/CR3022. We also highlight public classes different protein. targeted present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent effective vaccines remains crucial combating future This review emphasizes importance identifying key utilizing antibody affinity maturation inform therapeutic design.

Language: Английский

Citations

2