AlphaFold2-Enabled Atomistic Modeling of Structure, Conformational Ensembles, and Binding Energetics of the SARS-CoV-2 Omicron BA.2.86 Spike Protein with ACE2 Host Receptor and Antibodies: Compensatory Functional Effects of Binding Hotspots in Modulating Mechanisms of Receptor Binding and Immune Escape DOI
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(5), P. 1657 - 1681

Published: Feb. 19, 2024

The latest wave of SARS-CoV-2 Omicron variants displayed a growth advantage and increased viral fitness through convergent evolution functional hotspots that work synchronously to balance requirements for productive receptor binding efficient immune evasion. In this study, we combined AlphaFold2-based structural modeling approaches with atomistic simulations mutational profiling energetics stability prediction comprehensive analysis the structure, dynamics, BA.2.86 spike variant ACE2 host distinct classes antibodies. We adapted several AlphaFold2 predict both structure conformational ensembles protein in complex receptor. results showed AlphaFold2-predicted ensemble can accurately capture main states variant. Complementary predictions, microsecond molecular dynamics reveal details landscape produced equilibrium structures are used perform scanning residues characterize energy hotspots. ensemble-based domain BA.2 complexes revealed group conserved hydrophobic critical variant-specific contributions R403K, F486P, R493Q. To examine evasion properties detail, performed structure-based interfaces antibodies significantly reduced neutralization against basis compensatory effects hotspots, showing lineage may have evolved outcompete other subvariants by improving while preserving affinity via effect R493Q F486P This study demonstrated an integrative approach combining predictions complementary robust enable accurate characterization mechanisms newly emerging variants.

Language: Английский

Immune evasion and ACE2 binding affinity contribute to SARS-CoV-2 evolution DOI
Wentai Ma, Haoyi Fu, Fanchong Jian

et al.

Nature Ecology & Evolution, Journal Year: 2023, Volume and Issue: 7(9), P. 1457 - 1466

Published: July 13, 2023

Language: Английский

Citations

54
Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion DOI Creative Commons

Song Xue,

Yuru Han, Fan Wu

et al.

Protein & Cell, Journal Year: 2024, Volume and Issue: 15(6), P. 403 - 418

Published: March 4, 2024

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within receptor binding domain (RBD) spike (S) protein, lead to functional alteration both engagement monoclonal antibody (mAb) recognition. Here, we review data RBD point mutations possessed by major discuss their individual effects on ACE2 affinity immune evasion. Many single amino acid substitutions epitopes crucial for evasion capacity may conversely weaken affinity. However, this weakened effect could be largely compensated specific epistatic such as N501Y, thus maintaining overall protein all variants. The predominant direction evolution lies neither promoting nor evading mAb neutralization but a delicate balance between these two dimensions. Together, interprets how efficiently resist meanwhile is maintained, emphasizing significance comprehensive assessment mutations.

Language: Английский

Citations

21
Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins DOI Creative Commons
Weiwei Li, Zepeng Xu, Tianhui Niu

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(8), P. 1484 - 1498

Published: March 11, 2024

Abstract Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and the recently emerged BA.2.86 JN.1. Receptor binding immune evasion are recognized as two major drivers for evolution of receptor domain (RBD) spike (S) protein. However, underlying mechanism interplay between factors remains incompletely understood. Herein, we determined structures human ACE2 complexed with XBB RBDs. Based on ACE2/RBD these sub-variants a comparison known complex structures, found that R346T substitution in RBD enhanced upon an interaction residue R493, but not Q493, via involving long-range conformation changes. Furthermore, R493Q F486V exert balanced impact, through which capability was somewhat compromised to achieve optimal binding. We propose “two-steps-forward one-step-backward” model describe such compromise affinity during sub-variants.

Language: Английский

Citations

21
Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1 DOI Creative Commons
Fanchong Jian, Jing Wang, Ayijiang Yisimayi

et al.

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

Published: April 22, 2024

Abstract The continuous evolution of SARS-CoV-2, particularly the emergence BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation current vaccine compositions. Here, we provide a comprehensive analysis humoral immune response to and JN.1 human exposures, emphasizing need for JN.1-lineage-based boosters. We demonstrate antigenic distinctiveness lineages in SARS-CoV-2-naive individuals but not those with prior vaccinations or infections, infection elicits superior plasma neutralization titers against its subvariants. highlight strong evasion receptor binding capability KP.3, supporting foreseeable prevalence. Extensive BCR repertoire, isolating ∼2000 RBD-specific monoclonal antibodies (mAbs) their targeting epitopes characterized by deep mutational scanning (DMS), underscores systematic superiority JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing (NAbs) contribute majorly within wildtype (WT)-reactive NAbs JN.1. However, KP.2 KP.3 evade substantial subset them, even induced JN.1, advocating booster updates optimized enrichment. JN.1-induced Omicron-specific also high potency across all Omicron lineages. Escape hotspots these have mainly been mutated RBD, resulting higher barrier escape, considering probable recovery previously escaped NAbs. Additionally, prevalence broadly reactive IGHV3-53/3-66- encoding MBCs, competing suggests inhibitory role on de novo activation naive cells, potentially explaining heavy imprinting mRNA-vaccinated individuals. These findings delineate evolving antibody shift from importance developing lineage, especially KP.3-based boosters, enhance immunity future SARS-CoV-2 variants.

Language: Английский

Citations

20
Spike structures, receptor binding, and immune escape of recently circulating SARS-CoV-2 Omicron BA.2.86, JN.1, EG.5, EG.5.1, and HV.1 sub-variants DOI
Linjie Li, Kaiyuan Shi,

Yuhang Gu

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(8), P. 1055 - 1067.e6

Published: July 15, 2024

Language: Английский

Citations

18
A unified evolution-driven deep learning framework for virus variation driver prediction DOI
Zhiwei Nie, Xudong Liu, Jie Chen

et al.

Nature Machine Intelligence, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

Citations

2
Using big sequencing data to identify chronic SARS-Coronavirus-2 infections DOI Creative Commons
Sheri Harari, Danielle Miller,

Shay Fleishon

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 20, 2024

Language: Английский

Citations

12
SARS-CoV-2 Omicron Subvariants Do Not Differ Much in Binding Affinity to Human ACE2: A Molecular Dynamics Study DOI Creative Commons
Hoang Linh Nguyen, Thai Quoc Nguyen, Mai Suan Li

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3340 - 3349

Published: April 2, 2024

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbates COVID-19 pandemic due to its high contagious ability. Studies have shown that binds human ACE2 more strongly than wild type. prevalence in new cases promotes novel lineages with improved receptor binding affinity and immune evasion. To shed light on this open problem, work, we investigated free energy domain BA.2, BA.2.3.20, BA.3, BA4/BA5, BA.2.75, BA.2.75.2, BA.4.6, XBB.1, XBB.1.5, BJ.1, BN.1, BQ.1.1, CH.1.1 using all-atom molecular dynamics simulation mechanics Poisson–Boltzmann surface area method. results show these increased compared BA.1 lineage, BA.2.75 BA.2.75.2 subvariants bind others. However, general, affinities do not differ significantly from each other. electrostatic force dominates over van der Waals interaction between cells. Based our results, argue viral evolution does further improve SARS-CoV-2 for but may increase

Language: Английский

Citations

11
Deep mutational scanning of SARS-CoV-2 Omicron BA.2.86 and epistatic emergence of the KP.3 variant DOI Creative Commons
Ashley L. Taylor, Tyler N. Starr

Virus Evolution, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 1, 2024

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements effects on traits, but epistatic shifts impacts mutations can hinder when were made outdated strain backgrounds. Here, we report impact all single amino acid ACE2-binding affinity protein folding expression SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain. As with other variants, find a plastic evolvable basis for receptor binding, many at ACE2 interface maintaining or even improving affinity. Despite its large genetic divergence, have not diverged greatly from those measured BA.2 ancestor. However, do identify strong positive epistasis among subsequent that accrued descendants. Specifically, Q493E mutation decreased previous backgrounds is reversed sign to enhance human coupled L455S F456L currently emerging KP.3 variant. Our results point modest degree drift during recent highlight how these small important consequences emergence new variants.

Language: Английский

Citations

10
Classification of five SARS-CoV-2 serotypes based on RBD antigenicities DOI Creative Commons
Shixiong Hu, Chunli Wu, Xinkai Wu

et al.

Science Bulletin, Journal Year: 2023, Volume and Issue: 68(23), P. 3003 - 3012

Published: Oct. 4, 2023

The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a significant number variants, particularly with the emergence Omicron many sub-variants. These variants have exhibited increased immune escape, leading to reduced efficacy existing vaccines and therapeutic antibodies. Given diminished cross-neutralization observed among these it is plausible that SARS-CoV-2 developed multiple serotypes. As major antigenic site, receptor-binding domain (RBD) viral spike (S) protein was chosen for serotyping. We selected 23 representative including pre-Omicron sub-variants, classified them into five serotypes based on systematic evaluation antigenicities their RBDs. Each serotype includes several genetically distinct variants. Serotype-I encompasses all (with two subtypes), while remaining four are comprised sub-variants at different stages evolution. propose can serve as foundation rapid classification newly emerging guide development future broad-spectrum neutralizing antibodies against disease 2019 (COVID-19).

Language: Английский

Citations

18