AlphaFold2-Enabled Atomistic Modeling of Epistatic Binding Mechanisms for the SARS-CoV-2 Spike Omicron XBB.1.5, EG.5 and FLip Variants: Convergent Evolution Hotspots Cooperate to Control Stability and Conformational Adaptability in Balancing ACE2 Binding and Antibody Resistance DOI Open Access
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 12, 2023

Abstract In this study, we combined AI-based atomistic structural modeling and microsecond molecular simulations of the SARS-CoV-2 Spike complexes with host receptor ACE2 for XBB.1.5+L455F, XBB.1.5+F456L(EG.5) XBB.1.5+L455F/F456L (FLip) lineages to examine mechanisms underlying role convergent evolution hotspots in balancing binding antibody evasion. Using ensemble-based mutational scanning spike protein residues physics-based rigorous computations affinities, identified energy characterized basis epistatic couplings between hotspots. Consistent experiments, results revealed mediating Q493 hotspot synchronization L455F F456L mutations providing a quantitative insight into mechanism differences XBB lineages. Mutational profiling is network-based model showing that Q493, L455 F456 sites mediate stable communities at interface can serve as mediators non-additive couplings. Structure-based analysis class 1 antibodies quantified critical F486P eliciting strong immune evasion response. The support which emergence EG.5 FLip variants may have been dictated by leveraging effects several revolutionary provide synergy improved broad neutralization resistance. This interpretation consistent notion functionally balanced substitutions simultaneously optimize high affinity continue emerge through beneficial pair or triplet combinations RBD involving highly adaptable regions.

Language: Английский

Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape DOI Open Access
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4281 - 4281

Published: April 12, 2024

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with host cell receptor ACE2 and panel diverse class one antibodies. The central objective investigation was to examine molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing antibody evasion variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, XBB.1.5 + L455F/F456L. By combining evolutionary analysis, dynamics simulations, ensemble-based mutational scanning protein residues in complexes ACE2, identified structural stability affinity are consistent results biochemical studies. agreement deep experiments, our quantitative analysis correctly reproduced strong variant-specific effects BA.2 variants. It shown Y453W F456L mutations can enhance when coupled Q493 while these become destabilized R493 position variant. provided rationale mechanism variants, showing role Q493/R493 hotspot modulating between sites L455F lineages. receptors antibodies provide experimental evidence interactions physically proximal Y501, R498, Q493, L455F, determine binding, F486P instrumental mediating broad resistance. supports which impact on is mediated through small group universal hotspots, effect immune could be more variant-dependent modulated by conformationally adaptable regions.

Language: Английский

Citations

8
The value of protein allostery in rational anticancer drug design: an update DOI Creative Commons
Ruth Nussinov, Hyunbum Jang

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(9), P. 1071 - 1085

Published: July 28, 2024

Introduction Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from into which ligand dock and do not account for exactly how site is altered. Favorable inhibitors nearby follow nature, mimicking diverse regulation strategies.

Language: Английский

Citations

8
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 DOI Open Access
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

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

Citations

7
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 DOI
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

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

Citations

5
Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking DOI Open Access

Grace Gupta,

Gennady M. Verkhivker

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4955 - 4955

Published: May 1, 2024

Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite increasing interest and effort in discovering inhibitors viral activity interactions with host receptor ACE2. The challenges modulators proteins are associated diversity cryptic sites complex molecular that can be employed by ligands, including alteration conformational equilibrium protein preferential stabilization specific functional states. In current study, we combine dynamics analysis distinct forms full-length trimers machine-learning-based binding pocket detection ensemble-based ligand docking free energy to characterize potential determine structural energetic determinants inhibition a series experimentally validated molecules. results demonstrate good agreement between computational experimental affinities, providing support predicted modes suggesting key formed ligands elicit observed inhibition. We establish known molecules, indicating mechanism modulation targeting hinges inter-protomer movements blocking changes closed open trimer forms. this study combining states rigorous enables robust characterization modes, identification hotspots, prediction affinities modulators, which is consistent data. This suggested adaptability bound conformations both play enable efficient interfere changes.

Language: Английский

Citations

3
Editorial for SARS-CoV-2 and COVID-19 Topical Collection DOI Creative Commons
Luis Martínez‐Sobrido, Fernando Almazán

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 356 - 356

Published: Feb. 25, 2024

A previously unknown coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was isolated in Wuhan, China December 2019, from a patient with disease linked to potential contact wild animals [...]

Language: Английский

Citations

0
Accurate Characterization of Conformational Ensembles and Binding Mechanisms of the SARS-CoV-2 Omicron BA.2 and BA.2.86 Spike Protein with the Host Receptor and Distinct Classes of Antibodies Using AlphaFold2-Augmented Integrative Computational Modeling DOI Open Access
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 21, 2023

The latest wave SARS-CoV-2 Omicron variants displayed a growth advantage and the increased viral fitness through convergent evolution of 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 all-atom MD simulations mutational profiling energetics stability prediction comprehensive analysis 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 dynamics signatures obtained from microscond molecular simulations. ensemble-based dynamic scanning domain residues BA.2 complexes dissected role backgrounds modulating free energy changes revealing group conserved hydrophobic critical variant-specific contributions sites R403K, F486P R493Q. To examine evasion properties atomistic detail, performed large scale structure-based S interfaces antibodies significantly reduced neutralization against variant. quantified specific function mutations ensure broad resistance different RBD This study revealed basis compensatory effects hotspots, showing lineage may have primarily evolved improve escape while affinity cooperative effect R493Q mutations. supports hypothesis impact on is more universal mediated cross-talk between could be variant-dependent.

Language: Английский

Citations

0
AlphaFold2-Enabled Atomistic Modeling of Epistatic Binding Mechanisms for the SARS-CoV-2 Spike Omicron XBB.1.5, EG.5 and FLip Variants: Convergent Evolution Hotspots Cooperate to Control Stability and Conformational Adaptability in Balancing ACE2 Binding and Antibody Resistance DOI Open Access
Nishank Raisinghani, Mohammed Alshahrani,

Grace Gupta

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 12, 2023

Abstract In this study, we combined AI-based atomistic structural modeling and microsecond molecular simulations of the SARS-CoV-2 Spike complexes with host receptor ACE2 for XBB.1.5+L455F, XBB.1.5+F456L(EG.5) XBB.1.5+L455F/F456L (FLip) lineages to examine mechanisms underlying role convergent evolution hotspots in balancing binding antibody evasion. Using ensemble-based mutational scanning spike protein residues physics-based rigorous computations affinities, identified energy characterized basis epistatic couplings between hotspots. Consistent experiments, results revealed mediating Q493 hotspot synchronization L455F F456L mutations providing a quantitative insight into mechanism differences XBB lineages. Mutational profiling is network-based model showing that Q493, L455 F456 sites mediate stable communities at interface can serve as mediators non-additive couplings. Structure-based analysis class 1 antibodies quantified critical F486P eliciting strong immune evasion response. The support which emergence EG.5 FLip variants may have been dictated by leveraging effects several revolutionary provide synergy improved broad neutralization resistance. This interpretation consistent notion functionally balanced substitutions simultaneously optimize high affinity continue emerge through beneficial pair or triplet combinations RBD involving highly adaptable regions.

Language: Английский

Citations

0