SARS-CoV-2 evolved variants optimize binding to cellular glycocalyx

Cell Reports Physical Science, Journal Year: 2023, Volume and Issue: 4(4), P. 101346 - 101346

Published: April 1, 2023

Viral variants of concern continue to arise for SARS-CoV-2, potentially impacting both methods detection and mechanisms action. Here, we investigate the effect an evolving spike positive charge in SARS-CoV-2 subsequent interactions with heparan sulfate angiotensin converting enzyme 2 (ACE2) glycocalyx. We show that positively charged Omicron variant evolved enhanced binding rates negatively Moreover, discover while spike-ACE2 affinity is comparable Delta variant, are significantly enhanced, giving rise a ternary complex spike-heparan sulfate-ACE2 large proportion double-bound triple-bound ACE2. Our findings suggest evolve be more dependent on viral attachment infection. This discovery enables us engineer second-generation lateral-flow test strip harnesses heparin ACE2 reliably detect all concern, including Omicron.

Language: Английский

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SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(14), P. 2747 - 2764.e7

Published: July 1, 2024

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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Electrostatic Features for the Receptor Binding Domain of SARS-COV-2 Wildtype and Its Variants. Compass to the Severity of the Future Variants with the Charge-Rule

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(36), P. 6835 - 6852

Published: Sept. 6, 2022

Electrostatic intermolecular interactions are important in many aspects of biology. We have studied the main electrostatic features involved interaction receptor-binding domain (RBD) SARS-CoV-2 spike protein with human receptor Angiotensin-converting enzyme 2 (ACE2). As principal computational tool, we used FORTE approach, capable to model proton fluctuations and computing free energies for a very large number protein–protein systems under different physical–chemical conditions, here focusing on RBD-ACE2 interactions. Both wild-type all critical variants included this study. From our ensemble extensive simulations, obtain, as function pH, binding affinities, charges proteins, their charge regulation capacities, dipole moments. In addition, calculated pKas ionizable residues mapped coupling between them. able present simple predictor based data obtained Alpha, Beta, Gamma, Delta, Omicron variants, linear correlation total RBD corresponding affinity. This "RBD rule" should work quick test degree severity coming future.

Language: Английский

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Changes in total charge on spike protein of SARS-CoV-2 in emerging lineages

Bioinformatics Advances, Journal Year: 2024, Volume and Issue: 4(1)

Published: Jan. 1, 2024

Abstract Motivation Charged amino acid residues on the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to influence its binding different cell surface receptors, non-specific electrostatic interactions with environment, and structural stability conformation. It is therefore important obtain a good understanding mutations that affect total charge which arisen across SARS-CoV-2 lineages during course virus’ evolution. Results We analyse change in number ionizable acids corresponding proteins almost 2200 emerged over span pandemic. Our results show previously observed trend toward an increase positive variants concern has essentially stopped emergence early omicron variants. Furthermore, recently greater diversity terms their composition acids. also demonstrate patterns are characteristic related within broader clade division phylogenetic tree. Due ubiquity biological our findings relevant for broad range studies dealing environment. Availability implementation The data underlying article available Supplementary material.

Language: Английский

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Predicting Functional Conformational Ensembles and Binding Mechanisms of Convergent Evolution for SARS-CoV-2 Spike Omicron Variants Using AlphaFold2 Sequence Scanning Adaptations and Molecular Dynamics Simulations

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

Published: April 3, 2024

Abstract In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles binding mechanisms convergent evolution the SARS-CoV-2 Spike Omicron variants BA.1, BA.2, BA.2.75, BA.3, BA.4/BA.5 BQ.1.1. We employed validated several different adaptations AlphaFold methodology including introduced randomized full sequence scanning manipulation variations systematically explore dynamics complexes with ACE2 receptor. Microsecond dynamic provide a detailed characterization landscapes thermodynamic stability variant complexes. By integrating predictions from applying statistical confidence metrics can expand identify functional conformations that determine equilibrium ACE2. Conformational RBD-ACE2 obtained using are accurate comparative prediction energetics revealing an excellent agreement experimental data. particular, results demonstrated AlphaFold-generated extended produce energies The study suggested complementarities potential synergies between showing information both methods potentially yield more adequate This provides insights in interplay binding, through acquisition mutational sites may leverage adaptability couplings key energy hotspots optimize affinity enable immune evasion.

Language: Английский

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AlphaFold2 Predictions of Conformational Ensembles and Atomistic Simulations of the SARS-CoV-2 Spike XBB Lineages Reveal Epistatic Couplings between Convergent Mutational Hotspots that Control ACE2 Affinity

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(19), P. 4696 - 4715

Published: May 2, 2024

In this study, we combined AlphaFold-based atomistic structural modeling, microsecond molecular simulations, mutational profiling, and network analysis to characterize binding mechanisms of the SARS-CoV-2 spike protein with host receptor ACE2 for a series Omicron XBB variants including XBB.1.5, XBB.1.5+L455F, XBB.1.5+F456L, XBB.1.5+L455F+F456L. dynamic modeling Spike lineages can accurately predict experimental structures conformational ensembles complexes ACE2. Microsecond dynamics simulations identified important differences in landscapes equilibrium variants, suggesting that combining AlphaFold predictions multiple conformations provide complementary approach characterization functional states mechanisms. Using ensemble-based profiling residues physics-based rigorous calculations affinities, energy hotspots characterized basis underlying epistatic couplings between convergent hotspots. Consistent experiments, results revealed mediating role Q493 hotspot synchronization L455F F456L mutations, providing quantitative insight into energetic determinants lineages. We also proposed network-based perturbation allosteric communications uncovered relationships centers long-range communication couplings. The study support mechanism which may be determined by effects evolutionary control binding.

Language: Английский

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Exploring Conformational Landscapes and Binding Mechanisms of Convergent Evolution for the SARS-CoV-2 Spike Omicron Variant Complexes with the ACE2 Receptor Using AlphaFold2-Based Structural Ensembles and Molecular Dynamics Simulations

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(25), P. 17720 - 17744

Published: Jan. 1, 2024

In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles evolution binding mechanisms convergent the SARS-CoV-2 spike Omicron variants BA.1, BA.2, BA.2.75, BA.3, BA.4/BA.5 BQ.1.1. We employed validated several different adaptations AlphaFold methodology including introduced randomized full sequence scanning manipulation variations systematically explore dynamics complexes with ACE2 receptor. Microsecond (MD) provide a detailed characterization landscapes thermodynamic stability variant complexes. By integrating predictions from applying statistical confidence metrics can expand identify functional conformations that determine equilibrium ACE2. Conformational RBD-ACE2 obtained using MD are accurate comparative prediction energetics revealing an excellent agreement experimental data. particular, results demonstrated AlphaFold-generated extended produce energies The study suggested complementarities potential synergies between showing information both methods potentially yield more adequate This provides insights in interplay binding, through acquisition mutational sites may leverage adaptability dynamic couplings key energy hotspots optimize affinity enable immune evasion.

Language: Английский

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Temperature-dependent Spike-ACE2 interaction of Omicron subvariants is associated with viral transmission

mBio, Journal Year: 2024, Volume and Issue: 15(8)

Published: July 2, 2024

The continued evolution of severe acute respiratory syndrome 2 (SARS-CoV-2) requires persistent monitoring its subvariants. Omicron subvariants are responsible for the vast majority SARS-CoV-2 infections worldwide, with XBB and BA.2.86 sublineages representing more than 90% circulating strains as January 2024. To better understand parameters involved in viral transmission, we characterized functional properties Spike glycoproteins from BA.2.75, CH.1.1, DV.7.1, BA.4/5, BQ.1.1, XBB, XBB.1, XBB.1.16, XBB.1.5, FD.1.1, EG.5.1, HK.3, JN.1. We tested their capacity to evade plasma-mediated recognition neutralization, binding angiotensin-converting enzyme (ACE2), susceptibility cold inactivation, processing, well impact temperature on Spike-ACE2 interaction. found that compared early wild-type (D614G) strain, most subvariants' evolved escape neutralization by plasma individuals who received a fifth dose bivalent (BA.1 or BA.4/5) mRNA vaccine improve ACE2 binding, particularly at low temperatures. Moreover, had best affinity all temperatures tested. processing is associated inactivation. Intriguingly, was significantly growth rates humans. Overall, report Spikes newly emerged relatively stable resistant present improved which associated, temperatures, rates.IMPORTANCEThe gave rise wide range variants harboring new mutations glycoproteins. Several factors have been transmission fitness such plasma-neutralization whether additional could be importance variants' characterize several glycoprotein presents an further temperature. interaction strongly rate, such, represent another parameter affecting transmission.

Language: Английский

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