How SARS-CoV-2 alters the regulation of gene expression in infected cells† DOI Creative Commons
Emmanuelle Bignon, Stéphanie Grandemange, Élise Dumont

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 19, 2022

Non-structural accessory proteins in viruses play a key role hijacking the basic cellular mechanisms, which is essential to promote virus survival and evasion of immune system. The immonuglobulin-like open reading frame 8 (ORF8) protein expressed by SARS-CoV-2 accumulates nucleus may influence regulation gene expression infected cells. In this contribution, using micro-second time-scale all-atom molecular dynamics simulations, we unravel structural bases behind epigenetic action ORF8. particular, highlight how able form stable aggregates with DNA through histone tail-like motif, interaction influenced post-translational modifications, such as acetylation methylation, are known markers histones. Our work not only clarifies mechanisms perturbation caused viral infection, but also offers an unusual perspective foster development original antivirals.

Language: Английский

Is Metal Stabilization of the Leaving Group Required or Can Lysine Facilitate Phosphodiester Bond Cleavage in Nucleic Acids? A Computational Study of EndoV DOI
Rajwinder Kaur, Stacey D. Wetmore

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(3), P. 944 - 959

Published: Jan. 22, 2024

Endonuclease V (EndoV) is a single-metal-dependent enzyme that repairs deaminated DNA nucleobases in cells by cleaving the phosphodiester bond, and this has proven to be powerful tool biotechnology medicine. The catalytic mechanism used EndoV must understood design new disease detection therapeutic solutions further exploit interdisciplinary applications. This study mixed molecular dynamics (MD) quantum mechanics/molecular mechanics (QM/MM) approach compare eight distinct pathways provides first proposed for bacterial EndoV. calculations demonstrate mechanisms involving either direct or indirect metal coordination leaving group of substrate previously other nucleases are unlikely EndoV, regardless general base (histidine, aspartate, phosphate moiety). Instead, characterized involve K139 stabilizing group, metal-coordinated water transition structure, H214 activating nucleophile. In silico K139A H214A mutational results support newly roles these residues. Although unseen combination base, acid, metal-binding architecture one-metal-dependent endonuclease, our fully consistent with experimental kinetic, structural, data. addition substantiating growing body literature, suggesting one enough catalyze P–O bond cleavage nucleic acids, fundamental understanding function will promote exploration improved applications

Language: Английский

Citations

5
Viral RNA Replication Suppression of SARS-CoV-2: Atomistic Insights into Inhibition Mechanisms of RdRp Machinery by ddhCTP DOI
Giada Ciardullo, Angela Parise, Mario Prejanò

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(5), P. 1593 - 1604

Published: Feb. 27, 2024

The nonstructural protein 12, known as RNA-dependent RNA polymerase (RdRp), is essential for both replication and repair of the viral genome. RdRp SARS-CoV-2 has been used a promising candidate drug development since inception COVID-19 spread. In this work, we performed an

Language: Английский

Citations

5
Structural Biology of the SARS-CoV-2 replication–transcription complex DOI Creative Commons
Cameron D. Fyfe, Cromarte Rogers, Alexander Matthew Payne

et al.

Crystallography Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 20

Published: March 18, 2025

Language: Английский

Citations

0
Binding Mechanism of the Active Form of Molnupiravir to RdRp of SARS-CoV-2 and Designing Potential Analogues: Insights from Molecular Dynamics Simulations DOI Creative Commons
Justin Carbone, Nicholas J. Paradis, Dylan Brunt

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(40), P. 41583 - 41598

Published: Sept. 24, 2024

Molnupiravir, an FDA-approved nucleoside prodrug for treating COVID-19, converts into N4-hydroxycytidine triphosphate (NHC-TP), which integrates SARS-CoV-2 RNA by its RNA-dependent polymerase (RdRp) causing lethal mutations in viral proteins. Due to the risk of RdRp-mediated drug resistance and potential off-target effects on host polymerases (e.g., human II/HPolII), it is crucial understand NHC-TP interactions at active sites developing new, resistance-proof treatments. In this study, we used molecular dynamics (MD) simulations probe key between RdRp designed novel analogues with greater selectivity over HPolII a virtual screening workflow. We docked modified RdRp-Remdesivir structure (PDB ID: 7BV2) generated 71 bulky substituents increase interaction RdRP reduce incorporation. MD assessed stability, binding affinity, site these analogues. The top 7 candidates, favorable ADMET properties, likely inhibit replication via dual mechanisms (the replicative stalling induction mutations) while maintaining RdRp.

Language: Английский

Citations

2
On the Recognition of Natural Substrate CTP and Endogenous Inhibitor ddhCTP of SARS-CoV-2 RNA-Dependent RNA Polymerase: A Molecular Dynamics Study DOI Creative Commons
Angela Parise, Giada Ciardullo, Mario Prejanò

et al.

Journal of Chemical Information and Modeling, Journal Year: 2022, Volume and Issue: 62(20), P. 4916 - 4927

Published: Oct. 11, 2022

The novel coronavirus SARS-CoV-2 is the causative agent of COVID-19 outbreak that affecting entire planet. As pandemic still spreading worldwide, with multiple mutations virus, it interest and help to employ computational methods for identifying potential inhibitors enzymes responsible viral replication. Attractive antiviral nucleotide analogue RNA-dependent RNA polymerase (RdRp) chain terminator are investigated this purpose. This study, based on molecular dynamics (MD) simulations, addresses important aspects incorporation an endogenously synthesized nucleoside triphosphate, ddhCTP, in comparison natural nucleobase cytidine triphosphate (CTP) RdRp. ddhCTP species product viperin protein as part innate immune response. absence ribose 3′-OH could have implications its inhibitory mechanism We built silico model strand embedded RdRp using experimental methods, starting from cryo-electron microscopy structure exploiting information obtained by spectrometry sequence. determined was stable during MD simulation time. results provide deeper insights into triphosphates, whose active site remains elusive.

Language: Английский

Citations

9
Resolving a guanine-quadruplex structure in the SARS-CoV-2 genome through circular dichroism and multiscale molecular modeling DOI Creative Commons
Luisa D’Anna, Tom Miclot, Emmanuelle Bignon

et al.

Chemical Science, Journal Year: 2023, Volume and Issue: 14(41), P. 11332 - 11339

Published: Jan. 1, 2023

The genome of SARS-CoV-2 coronavirus is made up a single-stranded RNA fragment that can assume specific secondary structure, whose stability influence the virus's ability to reproduce. Recent studies have identified putative guanine quadruplex sequences in fragments are involved coding for both structural and non-structural proteins. In this contribution, we focus on G-rich sequence referred as RG-2, which codes protein 10 (Nsp10) assumes guanine-quadruplex (G4) arrangement. We provide structure RG-2 G4 at atomistic resolution by molecular modeling simulation, validated superposition experimental calculated electronic circular dichroism spectra. Through simulation approaches, demonstrated pyridostatin (PDS), widely recognized binder, bind stabilize more strongly than RG-1, another forming was previously proposed potential target antiviral drug candidates. Overall, study highlights valuable inhibit translation replication SARS-CoV-2, paving way towards original therapeutic approaches against emerging viruses.

Language: Английский

Citations

4
SARS-CoV-2 RNA-Dependent RNA Polymerase Follows Asynchronous Translocation Pathway for Viral Transcription and Replication DOI
Xiaowei Wang, Tiantian Xu, Yuan Yao

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(45), P. 10119 - 10128

Published: Nov. 3, 2023

Translocation is one essential step for the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) to exert viral replication and transcription. Although cryo-EM structures of RdRp are available, molecular mechanisms dynamic translocation remain elusive. Herein, we constructed a Markov state model based on extensive dynamics simulations elucidate RdRp. We identified two intermediates that pinpoint rate-limiting characterize asynchronous movement template-primer duplex. The 3′-terminal nucleotide in primer strand lags behind due uneven distribution protein–RNA interactions, while template delayed by hurdle residue K500. Even so, strands share same "ratchet" stabilize post-translocation state, suggesting Brownian-ratchet model. Overall, our study provides intriguing insights into transcription, which would open new avenue drug discoveries.

Language: Английский

Citations

4
Simulations predict preferred Mg2+ coordination in a nonenzymatic primer extension reaction center DOI Creative Commons
Shriyaa Mittal, Collin Nisler, Jack W. Szostak

et al.

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(12), P. 1579 - 1591

Published: May 3, 2024

The mechanism by which genetic information was copied prior to the evolution of ribozymes is great interest because its importance origin life. most effective known process for nonenzymatic copying an RNA template primer extension a two-step pathway in 2-aminoimidazole-activated nucleotides first react with each other form imidazolium-bridged intermediate that subsequently reacts primer. Reaction kinetics, structure-activity relationships, and X-ray crystallography have provided insight into overall reaction mechanism, but many puzzles remain. In particular, high concentrations Mg

Language: Английский

Citations

1
How SARS-CoV-2 Alters the Regulation of Gene Expression in Infected Cells DOI Open Access
Emmanuelle Bignon, Stéphanie Grandemange, Élise Dumont

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(13), P. 3199 - 3207

Published: March 27, 2023

Nonstructural accessory proteins in viruses play a key role hijacking the basic cellular mechanisms, which is essential to promote virus survival and evasion of immune system. The immonuglobulin-like open reading frame 8 (ORF8) protein expressed by SARS-CoV-2 accumulates nucleus may influence regulation gene expression infected cells. In this contribution, using microsecond time-scale all-atom molecular dynamics simulations, we unravel structural bases behind epigenetic action ORF8. particular, highlight how able form stable aggregates with DNA through histone tail-like motif, interaction influenced post-translational modifications, such as acetylation methylation, are known markers histones. Our work not only clarifies mechanisms perturbation caused viral infection but also offers an unusual perspective foster development original antivirals.

Language: Английский

Citations

2
Exploring the covalent inhibition mechanisms of inhibitors with two different warheads acting on SARS-CoV-2 Mpro by QM/MM simulations DOI
Xiaoyue Yang,

Mengguo Chen,

Fanru Yuan

et al.

Computational and Theoretical Chemistry, Journal Year: 2024, Volume and Issue: 1242, P. 114979 - 114979

Published: Nov. 5, 2024

Language: Английский

Citations

0