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

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(43)

Опубликована: Окт. 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.

Язык: Английский

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COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein

Biology Direct, Год журнала: 2020, Номер 15(1)

Опубликована: Окт. 16, 2020

The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much this research focus centered on ectodomain protein. is anchored a transmembrane region, followed by cytoplasmic tail. Here we report distant sequence similarity between cysteine-rich tail coronavirus protein hepcidin that found in humans other vertebrates. Hepcidin thought be key regulator iron metabolism humans. An implication preliminary observation suggest route investigation field making use an already-established literature interplay local systemic regulation, cytokine-mediated inflammatory processes, respiratory infections question possible homology evolutionary connection viral not assessed report, but some scenarios study are discussed.

Язык: Английский

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Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Journal of Proteome Research, Год журнала: 2020, Номер 19(11), С. 4587 - 4608

Опубликована: Окт. 2, 2020

The development of computational strategies for the quantitative characterization functional mechanisms SARS-CoV-2 spike proteins is paramount importance in efforts to accelerate discovery novel therapeutic agents and vaccines combating COVID-19 pandemic. Structural biophysical studies have recently characterized conformational landscapes glycoproteins prefusion form, revealing a spectrum stable more dynamic states. By employing molecular simulations network modeling approaches, this study systematically examined dynamics identified regulatory centers allosteric interactions distinct states wild-type mutant variants trimer. This presents evidence that protein can function as an engine fluctuates between dynamically Perturbation-based interaction networks revealed key role cross-talk effector hotspots receptor binding domain fusion peptide proximal region protein. results shown control switching are associated with virus entry host receptor. offers useful perspective on underlying through lens signaling apparatus transmission could open up opportunities targeted drug against contribute rapid response current potential future pandemic scenarios.

Язык: 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, Год журнала: 2021, Номер 60(19), С. 1459 - 1484

Опубликована: Апрель 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.

Язык: 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, Год журнала: 2021, Номер 125(18), С. 4596 - 4619

Опубликована: Апрель 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.

Язык: Английский

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Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

The Journal of Physical Chemistry B, Год журнала: 2021, Номер 125(3), С. 850 - 873

Опубликована: Янв. 15, 2021

The rapidly growing body of structural and biochemical studies the SARS-CoV-2 spike glycoprotein has revealed a variety distinct functional states with radically different arrangements receptor-binding domain, highlighting remarkable function-driven conformational plasticity adaptability proteins. In this study, we examined molecular mechanisms underlying dynamic changes in mutant trimers through lens analysis allosteric interaction networks atomistic modeling signal transmission. Using an integrated approach that combined coarse-grained simulations, protein stability analysis, perturbation-based residue networks, how mutations regulatory regions can differentially affect dynamics signaling states. results study key centers govern collective dynamics, interactions, control transmission We found experimentally confirmed hotspots dictate switching between correspond to hinge sites global mediating networks. provide novel insight into proteins showing at positions modulate distribution determine topography communication pathways operating state-specific cascades switch points. This provides plausible strategy for probing equilibrium therapeutic intervention by targeting specific interactions communications

Язык: Английский

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Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

Chemical Reviews, Год журнала: 2022, Номер 122(13), С. 11287 - 11368

Опубликована: Май 20, 2022

Despite tremendous efforts in the past two years, our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), virus-host interactions, immune response, virulence, transmission, and evolution is still very limited. This limitation calls for further in-depth investigation. Computational studies have become an indispensable component combating disease 2019 (COVID-19) due to their low cost, efficiency, fact that they are free from safety ethical constraints. Additionally, mechanism governs global transmission SARS-CoV-2 cannot be revealed individual experiments was discovered by integrating genotyping massive viral sequences, biophysical modeling protein-protein deep mutational data, learning, advanced mathematics. There exists a tsunami literature on molecular modeling, simulations, predictions related developments drugs, vaccines, antibodies, diagnostics. To provide readers with quick update about this literature, we present comprehensive systematic methodology-centered review. Aspects such as biophysics, bioinformatics, cheminformatics, machine mathematics discussed. review will beneficial researchers who looking ways contribute those interested status field.

Язык: Английский

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SARS-CoV-2 mechanisms of cell tropism in various organs considering host factors

Heliyon, Год журнала: 2024, Номер 10(4), С. e26577 - e26577

Опубликована: Фев. 1, 2024

A critical step in the drug design for SARS-CoV-2 is to discover its molecular targets. This study comprehensively reviewed mechanisms of SARS-CoV-2, exploring host cell tropism and interaction targets crucial entry. The findings revealed that beyond ACE2 as primary entry receptor, alternative receptors, co-receptors, several proteases such TMPRSS2, Furin, Cathepsin L, ADAM play roles virus subsequent pathogenesis. Additionally, displays various human organs due diverse receptors. review delves into intricate details proteases, involvement each organ. Polymorphisms receptor mutations spike or RBD region contribute emergence variants like Alpha, Beta, Gamma, Delta, Omicron, impacting pathogenicity SARS-CoV-2. challenge posed by raises questions about effectiveness existing vaccines drugs, necessitating consideration updates their formulations. In urgency these situations, repurposed drugs Camostat Mesylate Nafamostat emerge viable pharmaceutical options. Numerous are involved inhibiting receptors factors entry, with most discussed this review. conclusion, may provide valuable insights inform decisions therapeutic approaches.

Язык: Английский

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Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveals the Allosteric Duality of Functionally Adaptable Hotspots

Journal of Chemical Theory and Computation, Год журнала: 2021, Номер 17(7), С. 4578 - 4598

Опубликована: Июнь 17, 2021

The functional adaptability and conformational plasticity of SARS-CoV-2 spike proteins allow for the efficient modulation complex phenotypic responses to host receptor antibodies. In this study, we combined atomistic simulations with mutational perturbation-based scanning approaches examine binding mechanisms three different classes ensemble-based profiling allosteric propensities protein residues showed that these can work as functionally adaptable allosterically regulated machines. Conformational dynamics analysis revealed binding-induced soft modes elicit unique response Mutational heatmaps sensitivity energy hotspots antibodies are consistent experimental deep mutagenesis, showing differences in affinity caused by global circulating variants positions K417, E484, N501 relatively moderate may not fully account observed antibody resistance effects. Through perturbation-response unbound form antibody-bound forms, how modulate determine control signal transmission changes. These results show targeted mutations correspond a group versatile centers which small perturbations collective motions, alter response, resistance. We suggest S exploit specific generate escape mutants without compromising activity protein.

Язык: Английский

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Systematic review on role of structure based drug design (SBDD) in the identification of anti-viral leads against SARS-Cov-2

Current Research in Pharmacology and Drug Discovery, Год журнала: 2021, Номер 2, С. 100026 - 100026

Опубликована: Янв. 1, 2021

The outbreak of existing public health distress is threatening the entire world with emergence and rapid spread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). novel disease 2019 (COVID-19) mild in most people. However, some elderly people co-morbid conditions, it may progress to pneumonia, (ARDS) multi organ dysfunction leading death. COVID-19 has caused global panic healthcare sector become one biggest threats economy. Drug discovery researchers are expected contribute rapidly than ever before. complete genome sequence had been reported barely a month after identification first patient. Potential drug targets combat treat infection have also explored. iterative structure-based design (SBDD) approach could significantly towards new like molecules for treatment COVID-19. antivirals experiences gained from SARS MERS outbreaks pave way potential using approach. SBDD momentum as essential tool faster costeffective lead past. FDA approved human immunodeficiency virus type 1 (HIV-1) inhibitors represent foremost success SBDD. This systematic review provides an overview coronavirus, its pathology replication, role structure based design, available recent advances in-silico prevention SARSCoV- main protease, RNA dependent polymerase (RdRp) spike (S) protein targets, which currently explored development.

Язык: Английский

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