Distant residues modulate conformational opening in SARS-CoV-2 spike protein

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(43)

Published: Oct. 6, 2021

Significance The novel coronavirus (SARS-CoV-2) pandemic resulted in the largest public health crisis recent times. Significant drug design effort against SARS-CoV-2 is focused on receptor-binding domain (RBD) of spike protein, although this region highly prone to mutations causing therapeutic resistance. We applied deep data analysis methods all-atom molecular dynamics simulations identify key non-RBD residues that play a crucial role spike−receptor binding and infection. Because are typically conserved across multiple coronaviruses, they can be targeted by broad-spectrum antibodies drugs treat infections from new strains might appear during future epidemics.

Language: Английский

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Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies: Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

Biochemistry, Journal Year: 2021, Volume and Issue: 60(19), P. 1459 - 1484

Published: April 26, 2021

In this study, we used an integrative computational approach to examine molecular mechanisms and determine functional signatures underlying the role of residues in SARS-CoV-2 spike protein that are targeted by novel mutational variants antibody-escaping mutations. Atomistic simulations dynamics analysis combined with alanine scanning sensitivity profiling complexes ACE2 host receptor REGN-COV2 antibody cocktail(REG10987+REG10933). Using analysis, have shown K417, E484, N501 correspond key interacting centers a significant degree structural energetic plasticity allow mutants these positions afford improved binding affinity ACE2. Through perturbation-based network modeling community ACE2, demonstrate E406, N439, serve as effector allosteric interactions anchor major intermolecular communities mediate long-range communication complexes. The results provide support model according which mutations constrained requirements for preservation stability may preferentially select structurally plastic energetically adaptable differentially modulate collective motions enzyme combination. This study suggests function versatile functionally machine exploits regulatory fine-tune response without compromising activity protein.

Language: Английский

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Integrated Biophysical Modeling of the SARS-CoV-2 Spike Protein Binding and Allosteric Interactions with Antibodies

The Journal of Physical Chemistry B, Journal Year: 2021, Volume and Issue: 125(18), P. 4596 - 4619

Published: April 30, 2021

Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity proteins capacity for eliciting specific binding broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, perturbation-based hierarchical network modeling SARS-CoV-2 protein a panel targeting distinct to explore mechanisms underlying binding-induced modulation dynamics allosteric signaling in proteins. Through analysis proteins, identified coevolving hotspots functional clusters that enable cross-talk between distant regions antibodies. Coarse-grained all-atom simulations combined mutational sensitivity mapping profiling receptor-binding domain (RBD) CR3022 CB6 enabled detailed validation proposed approach an extensive quantitative comparison experimental structural deep mutagenesis scanning data. By combining silico scanning, modeling, trimer H014, S309, S2M11, S2E12 antibodies, demonstrated can incur functionally relevant changes by modulating propensities collective The results provide novel insight into regulatory S showing antibody-escaping mutations preferentially target structurally adaptable energy effector centers control movements communication complexes.

Language: Английский

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Accelerating COVID-19 Research Using Molecular Dynamics Simulation

The Journal of Physical Chemistry B, Journal Year: 2021, Volume and Issue: 125(32), P. 9078 - 9091

Published: July 28, 2021

The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided opportunity make rational scientific breakthroughs in time crisis. Advancements these technologies recent years become an indispensable tool studying protein structure, function, dynamics, interactions, discovery. Integrating structural data obtained from high-resolution methods with MD helped comprehending process infection pathogenesis, well SARS-CoV-2 maturation host cells, short duration time. It also guided us identify prioritize targets new chemical entities, repurpose drugs. Here, we discuss how simulation been explored by community accelerate guide translational research on past year. We considered future directions researchers, where can help fill existing gaps research.

Language: Английский

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Multifaceted Computational Modeling in Glycoscience

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(20), P. 15914 - 15970

Published: July 5, 2022

Glycoscience assembles all the scientific disciplines involved in studying various molecules and macromolecules containing carbohydrates complex glycans. Such an ensemble involves one of most extensive sets quantity occurrence since they occur microorganisms higher organisms. Once compositions sequences these are established, determination their three-dimensional structural dynamical features is a step toward understanding molecular basis underlying properties functions. The range relevant computational methods capable addressing such issues anchored by specificity stereoelectronic effects from quantum chemistry to mesoscale modeling throughout dynamics mechanics coarse-grained docking calculations. Review leads reader through detailed presentations applications modeling. illustrations cover carbohydrate–carbohydrate interactions, glycolipids, N- O-linked glycans, emphasizing role SARS-CoV-2. presentation continues with structure polysaccharides solution solid-state lipopolysaccharides membranes. full protein-carbohydrate interactions presented, as exemplified carbohydrate-active enzymes, transporters, lectins, antibodies, glycosaminoglycan binding proteins. A final section list 150 tools databases help address many glycobioinformatics.

Language: Английский

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Protein conformational ensembles in function: roles and mechanisms

RSC Chemical Biology, Journal Year: 2023, Volume and Issue: 4(11), P. 850 - 864

Published: Jan. 1, 2023

The

Language: Английский

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Markov State Models and Perturbation-Based Approaches Reveal Distinct Dynamic Signatures and Hidden Allosteric Pockets in the Emerging SARS-Cov-2 Spike Omicron Variant Complexes with the Host Receptor: The Interplay of Dynamics and Convergent Evolution Modulates Allostery and Functional Mechanisms

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(16), P. 5272 - 5296

Published: Aug. 7, 2023

The new generation of SARS-CoV-2 Omicron variants displayed a significant growth advantage and increased viral fitness by acquiring convergent mutations, suggesting that the immune pressure can promote evolution leading to sudden acceleration evolution. In current study, we combined structural modeling, microsecond molecular dynamics simulations, Markov state models characterize conformational landscapes identify specific dynamic signatures spike complexes with host receptor ACE2 for recently emerged highly transmissible XBB.1, XBB.1.5, BQ.1, BQ.1.1 variants. Microsecond simulations Markovian modeling provided detailed characterization functional states revealed thermodynamic stabilization XBB.1.5 subvariant, which be contrasted more BQ.1 subvariants. Despite considerable similarities, mutations induce unique distributions states. results suggested variant-specific changes mobility in interfacial loops receptor-binding domain protein fine-tuned through crosstalk between could provide an evolutionary path modulation escape. By combining atomistic analysis perturbation-based approaches, determined important complementary roles mutation sites as effectors receivers allosteric signaling involved plasticity regulation communications. This study also hidden pockets control distribution flexible adaptable regions.

Language: Английский

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Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(5), P. 1413 - 1428

Published: Feb. 24, 2023

Allosteric mechanisms are commonly employed regulatory tools used by proteins to orchestrate complex biochemical processes and control communications in cells. The quantitative understanding characterization of allosteric molecular events among major challenges modern biology require integration innovative computational experimental approaches obtain atomistic-level knowledge the states, interactions, dynamic conformational landscapes. growing body studies empowered emerging artificial intelligence (AI) technologies has opened up new paradigms for exploring learning universe protein allostery from first principles. In this review we analyze recent developments high-throughput deep mutational scanning functions; applications latest adaptations Alpha-fold structural prediction methods dynamics allostery; frontiers integrating machine enhanced sampling techniques advances systems. We also highlight SARS-CoV-2 spike (S) revealing an important often hidden role regulation driving functional changes, binding interactions with host receptor, escape S which critical viral infection. conclude a summary outlook future directions suggesting that AI-augmented biophysical computer simulation beginning transform toward systematic landscapes, may bring about revolution drug discovery.

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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