SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1716 - 1716

Опубликована: Фев. 2, 2022

The review aims to consolidate research findings on the molecular mechanisms and virulence pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome 2 (SARS-CoV-2), their relevance four typical stages in development viral infection. These are invasion; primary blockade antiviral innate immunity; engagement virus’s protection against factors adaptive acute, long-term complications COVID-19. invasion stage entails recognition spike protein (S) SARS-CoV-2 target cell receptors, namely, main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, potential alternative receptors. presence a diverse repertoire receptors allows infect various types cells, including those not expressing ACE2. During second stage, majority polyfunctional structural, non-structural, extra proteins synthesizes infected cells involved blockage immunity. A high degree redundancy systemic action characterizing these pathogenic overcome at initial invasion. third includes passive active virus from immunity, overcoming barrier function focus inflammation, generalization body. fourth is associated with deployment variants SARS-CoV-2’s ability induce autoimmune autoinflammatory pathways tissue both immunosuppressive hyperergic inflammation critical this

Язык: Английский

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Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

PLoS Computational Biology, Год журнала: 2021, Номер 17(8), С. e1009286 - e1009286

Опубликована: Авг. 5, 2021

The SARS-CoV-2 Spike protein needs to be in an open-state conformation interact with ACE2 initiate viral entry. We utilise coarse-grained normal mode analysis model the dynamics of and calculate transition probabilities between states for 17081 variants including experimentally observed variants. Our results correctly increase occupancy more infectious D614G via flexibility closed-state decrease open-state. predict same effect several mutations on glycine residues (404, 416, 504, 252) as well K417, D467 N501, N501Y mutation recently within B.1.1.7, 501.V2 P1 strains. This is, our knowledge, first use conformational state transitions such transitions. specific identified here may guide future studies understanding infection mechanisms public health their surveillance efforts.

Язык: Английский

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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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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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Accelerating COVID-19 Research Using Molecular Dynamics Simulation

The Journal of Physical Chemistry B, Год журнала: 2021, Номер 125(32), С. 9078 - 9091

Опубликована: Июль 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.

Язык: 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, Год журнала: 2023, Номер 63(16), С. 5272 - 5296

Опубликована: Авг. 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.

Язык: Английский

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Mutational dynamics of SARS-CoV-2: Impact on future COVID-19 vaccine strategies

Heliyon, Год журнала: 2024, Номер 10(9), С. e30208 - e30208

Опубликована: Апрель 25, 2024

The rapid emergence of multiple strains Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has sparked profound concerns regarding the ongoing evolution virus and its potential impact on global health. Classified by World Health Organization (WHO) as variants concern (VOC), these exhibit heightened transmissibility pathogenicity, posing significant challenges to existing vaccine strategies. Despite widespread vaccination efforts, continual SARS-CoV-2 presents a formidable obstacle achieving herd immunity. Of particular is coronavirus spike (S) protein, pivotal viral surface protein crucial for host cell entry infectivity. Mutations within S have been shown enhance confer resistance antibody-mediated neutralization, undermining efficacy traditional platforms. Moreover, undergoes molecular under selective immune pressure, leading diverse with distinct mutation profiles. This review underscores urgent need vigilance adaptation in development efforts combat evolving landscape mutations ensure long-term effectiveness immunization campaigns.

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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