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Article: Cysteine hyperoxidation rewires communication pathways in the nucleosome and destabilizes the dyad.

Karami, Yasaman / Bignon, Emmanuelle

Computational and structural biotechnology journal

2024 Volume 23, Page(s) 1387–1396

Abstract: Gene activity is tightly controlled by reversible chemical modifications called epigenetic marks, which are of various types and modulate gene accessibility without affecting the DNA sequence. Despite an increasing body of evidence demonstrating the role ...

Abstract	Gene activity is tightly controlled by reversible chemical modifications called epigenetic marks, which are of various types and modulate gene accessibility without affecting the DNA sequence. Despite an increasing body of evidence demonstrating the role of oxidative-type modifications of histones in gene expression regulation, there remains a complete absence of structural data at the atomistic level to understand the molecular mechanisms behind their regulatory action. Owing to μs time-scale MD simulations and protein communication networks analysis, we describe the impact of histone H3 hyperoxidation (i.e., S-sulfonylation) on the nucleosome core particle dynamics. Our results reveal the atomic-scale details of the intrinsic structural networks within the canonical histone core and their perturbation by hyperoxidation of the histone H3 C110. We show that this modification involves local rearrangements of the communication networks and destabilizes the dyad, and that one modification is enough to induce a maximal structural signature. Our results suggest that cysteine hyperoxidation in the nucleosome core particle might favor its disassembly.
Language	English
Publishing date	2024-04-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2024.03.025
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Robust AMBER Force Field Parameters for Glutathionylated Cysteines.

Elftmaoui, Zineb / Bignon, Emmanuelle

International journal of molecular sciences

2023 Volume 24, Issue 19

Abstract: S-glutathionylation is an oxidative post-translational modification, which is involved in the regulation of many cell signaling pathways. Increasing amounts of studies show that it is crucial in cell homeostasis and deregulated in several pathologies. ... ...

Abstract	S-glutathionylation is an oxidative post-translational modification, which is involved in the regulation of many cell signaling pathways. Increasing amounts of studies show that it is crucial in cell homeostasis and deregulated in several pathologies. However, the effect of S-glutathionylation on proteins' structure and activity is poorly understood, and a drastic lack of structural information at the atomic scale remains. Studies based on the use of molecular dynamics simulations, which can provide important information about modification-induced modulation of proteins' structure and function, are also sparse, and there is no benchmarked force field parameters for this modified cysteine. In this contribution, we provide robust AMBER parameters for S-glutathionylation, which we tested extensively against experimental data through a total of 33 μs molecular dynamics simulations. We show that our parameter set efficiently describes the global and local structural properties of S-glutathionylated proteins. These data provide the community with an important tool to foster new investigations into the effect of S-glutathionylation on protein dynamics and function, in a common effort to unravel the structural mechanisms underlying its critical role in cellular processes.
MeSH term(s)	Cysteine/metabolism ; Glutathione/metabolism ; Proteins/metabolism ; Protein Processing, Post-Translational ; Signal Transduction ; Oxidation-Reduction
Chemical Substances	Cysteine (K848JZ4886) ; Glutathione (GAN16C9B8O) ; Proteins
Language	English
Publishing date	2023-10-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241915022
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Article ; Online: Modeling the Enzymatic Mechanism of the SARS-CoV-2 RNA-Dependent RNA Polymerase by DFT/MM-MD: An Unusual Active Site Leading to High Replication Rates.

Bignon, Emmanuelle / Monari, Antonio

Journal of chemical information and modeling

2022 Volume 62, Issue 17, Page(s) 4261–4269

Abstract: Viral infection relies on the hijacking of cellular machineries to enforce the reproduction of the infecting virus and its subsequent diffusion. In this context, the replication of the viral genome is a key step performed by specific enzymes, i.e., ... ...

Abstract	Viral infection relies on the hijacking of cellular machineries to enforce the reproduction of the infecting virus and its subsequent diffusion. In this context, the replication of the viral genome is a key step performed by specific enzymes, i.e., polymerases. The replication of SARS-CoV-2, the causative agent of the COVID-19 pandemics, is based on the duplication of its RNA genome, an action performed by the viral RNA-dependent RNA polymerase. In this contribution, by using highly demanding DFT/MM-MD computations coupled to 2D-umbrella sampling techniques, we have determined the chemical mechanisms leading to the inclusion of a nucleotide in the nascent viral RNA strand. These results highlight the high efficiency of the polymerase, which lowers the activation free energy to less than 10 kcal/mol. Furthermore, the SARS-CoV-2 polymerase active site is slightly different from those usually found in other similar enzymes, and in particular, it lacks the possibility to enforce a proton shuttle via a nearby histidine. Our simulations show that this absence is partially compensated by lysine whose proton assists the reaction, opening up an alternative, but highly efficient, reactive channel. Our results present the first mechanistic resolution of SARS-CoV-2 genome replication at the DFT/MM-MD level and shed light on its unusual enzymatic reactivity paving the way for the future rational design of antivirals targeting emerging RNA viruses.
MeSH term(s)	Antiviral Agents/pharmacology ; COVID-19 ; Catalytic Domain ; Humans ; Protons ; RNA, Viral/genetics ; RNA-Dependent RNA Polymerase ; SARS-CoV-2 ; Virus Replication
Chemical Substances	Antiviral Agents ; Protons ; RNA, Viral ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2022-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.2c00802
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Article ; Online: How SARS-CoV-2 Alters the Regulation of Gene Expression in Infected Cells.

Bignon, Emmanuelle / Grandemange, Stéphanie / Dumont, Elise / Monari, Antonio

The journal of physical chemistry letters

2023 Volume 14, Issue 13, Page(s) 3199–3207

Abstract: Nonstructural accessory proteins in viruses play a key role in hijacking the basic cellular mechanisms, which is essential to promote the virus survival and evasion of the immune system. The immonuglobulin-like open reading frame 8 (ORF8) protein ... ...

Abstract	Nonstructural accessory proteins in viruses play a key role in hijacking the basic cellular mechanisms, which is essential to promote the virus survival and evasion of the immune system. The immonuglobulin-like open reading frame 8 (ORF8) protein expressed by SARS-CoV-2 accumulates in the nucleus and may influence the regulation of the gene expression in infected cells. In this contribution, by using microsecond time-scale all-atom molecular dynamics simulations, we unravel the structural bases behind the epigenetic action of ORF8. In particular, we highlight how the protein is able to form stable aggregates with DNA through a histone tail-like motif, and how this interaction is influenced by post-translational modifications, such as acetylation and methylation, which are known epigenetic markers in histones. Our work not only clarifies the molecular mechanisms behind the perturbation of the epigenetic regulation caused by the viral infection but also offers an unusual perspective which may foster the development of original antivirals.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; Epigenesis, Genetic ; COVID-19/genetics ; Histones/metabolism ; Methylation
Chemical Substances	Histones
Language	English
Publishing date	2023-03-27
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.3c00582
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Molecular Basis of the pH-Controlled Maturation of the Tick-Borne Encephalitis Flavivirus.

Bignon, Emmanuelle / Dumont, Elise / Monari, Antonio

The journal of physical chemistry letters

2023 Volume 14, Issue 7, Page(s) 1977–1982

Abstract: Flaviviruses are enveloped viruses causing high public concerns. Their maturation spans several cellular compartments having different pH. Thus, complex control mechanisms are in place to avoid premature maturation. Here we report the dynamical behavior ... ...

Abstract	Flaviviruses are enveloped viruses causing high public concerns. Their maturation spans several cellular compartments having different pH. Thus, complex control mechanisms are in place to avoid premature maturation. Here we report the dynamical behavior at neutral and acidic pH of the precursor of the membrane fusion protein E of tick-borne encephalitis, showing the different stabilizations of the E dimer and the role played by the small fusion-assisting protomer (pr). The comprehension, at atomic resolution, of the fine regulation of viral maturation will be fundamental to the development of efficient strategies against emerging viral threats.
MeSH term(s)	Humans ; Encephalitis, Tick-Borne ; Encephalitis Viruses, Tick-Borne/chemistry ; Encephalitis Viruses, Tick-Borne/metabolism ; Viral Envelope Proteins/chemistry ; Viral Envelope Proteins/metabolism ; Flavivirus Infections ; Hydrogen-Ion Concentration
Chemical Substances	Viral Envelope Proteins
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.2c03551
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Binding to nucleosome poises human SIRT6 for histone H3 deacetylation.

Smirnova, Ekaterina / Bignon, Emmanuelle / Schultz, Patrick / Papai, Gabor / Ben Shem, Adam

eLife

2024 Volume 12

Abstract: Sirtuin 6 (SIRT6) is an ... ...

Abstract	Sirtuin 6 (SIRT6) is an NAD
MeSH term(s)	Humans ; Nucleosomes ; Histones ; NAD ; Chromatin ; Glycosyltransferases ; Histone Deacetylases ; DNA ; Sirtuins
Chemical Substances	Nucleosomes ; Histones ; NAD (0U46U6E8UK) ; Chromatin ; Glycosyltransferases (EC 2.4.-) ; Histone Deacetylases (EC 3.5.1.98) ; DNA (9007-49-2) ; SIRT6 protein, human (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.87989
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Article: Autophagy and evasion of the immune system by SARS-CoV-2. Structural features of the non-structural protein 6 from wild type and Omicron viral strains interacting with a model lipid bilayer.

Bignon, Emmanuelle / Marazzi, Marco / Grandemange, Stéphanie / Monari, Antonio

Chemical science

2022 Volume 13, Issue 20, Page(s) 6098–6105

Abstract: The viral cycle of SARS-CoV-2 is based on a complex interplay with the cellular machinery, which is mediated by specific proteins eluding or hijacking the cellular defense mechanisms. Among the complex pathways induced by the viral infection, autophagy ... ...

Abstract	The viral cycle of SARS-CoV-2 is based on a complex interplay with the cellular machinery, which is mediated by specific proteins eluding or hijacking the cellular defense mechanisms. Among the complex pathways induced by the viral infection, autophagy is particularly crucial and is strongly influenced by the action of the non-structural protein 6 (Nsp6) interacting with the endoplasmic reticulum membrane. Importantly, differently from other non-structural proteins, Nsp6 is mutated in the recently emerged Omicron variant, suggesting a possible different role of autophagy. In this contribution we explore, for the first time, the structural properties of Nsp6 thanks to long-timescale molecular dynamics simulations and machine learning analysis, identifying the interaction patterns with the lipid membrane. We also show how the mutation brought by the Omicron variant may indeed modify some of the specific interactions, and more particularly help anchor the viral protein to the lipid bilayer interface.
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d2sc00108j
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Article ; Online: Hijacking of Cellular Functions by Severe Acute Respiratory Syndrome Coronavirus-2. Permeabilization and Polarization of the Host Lipid Membrane by Viroporins.

Bignon, Emmanuelle / Marazzi, Marco / Monari, Antonio

The journal of physical chemistry letters

2022 Volume 13, Issue 21, Page(s) 4642–4649

Abstract: Like all viral infections, SARS-CoV-2 acts at multiple levels, hijacking fundamental cellular functions and assuring its replication and immune system evasion. In particular, the viral 3' Open Reading Frame (ORF3a) codes for a hydrophobic protein, which ... ...

Abstract	Like all viral infections, SARS-CoV-2 acts at multiple levels, hijacking fundamental cellular functions and assuring its replication and immune system evasion. In particular, the viral 3' Open Reading Frame (ORF3a) codes for a hydrophobic protein, which embeds in the cellular membrane, where it acts as an ion viroporin and is related to strong inflammatory response. Here we report equilibrium and enhanced sampling molecular dynamic simulation of the SARS-CoV-2 ORF3a in a model lipid bilayer, showing how the protein permeabilizes the lipid membrane, via the formation of a water channel, which in turn assures ion transport. We report the free energy profile for both K
MeSH term(s)	COVID-19 ; Cell Membrane/virology ; Humans ; Lipids ; SARS-CoV-2 ; Viroporin Proteins
Chemical Substances	Lipids ; Viroporin Proteins
Language	English
Publishing date	2022-05-20
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.2c01102
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Article ; Online: Synthesis of Original Cyclic Dinucleotide Analogues Using the Sulfo-click Reaction.

Amador, Romain / Vasseur, Jean-Jacques / Birkuš, Gabriel / Bignon, Emmanuelle / Monari, Antonio / Clavé, Guillaume / Smietana, Michael

Organic letters

2024 Volume 26, Issue 4, Page(s) 819–823

Abstract: The stimulator of interferon genes (STING) protein plays a crucial role in the activation of the innate immune response. Activation of STING is initiated by cyclic dinucleotides (CDNs) which prompted the community to synthesize structural analogues to ... ...

Abstract	The stimulator of interferon genes (STING) protein plays a crucial role in the activation of the innate immune response. Activation of STING is initiated by cyclic dinucleotides (CDNs) which prompted the community to synthesize structural analogues to enhance their biological properties. We present here the synthesis and biological evaluation of four novel CDN analogues composed of an
MeSH term(s)	Nucleotides, Cyclic/chemistry ; Nucleotides, Cyclic/metabolism ; Membrane Proteins/agonists ; Membrane Proteins/chemistry ; Click Chemistry/methods
Chemical Substances	Nucleotides, Cyclic ; STING1 protein, human ; Membrane Proteins
Language	English
Publishing date	2024-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/acs.orglett.3c03908
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Article ; Online: Unraveling the Enzymatic Mechanism of the SARS-CoV-2 RNA-Dependent-RNA-Polymerase. An Unusual Active Site Leading to High Replication Rates.

Bignon, Emmanuelle / Monari, Antonio

bioRxiv

Abstract: Viral infection relies on the hijacking of cellular machineries to enforce the reproduc- tion of the infecting virus and its subsequent diffusion. In this context the replication of the viral genome is a key step performed by specific enzymes, i.e. ... ...

Abstract	Viral infection relies on the hijacking of cellular machineries to enforce the reproduc- tion of the infecting virus and its subsequent diffusion. In this context the replication of the viral genome is a key step performed by specific enzymes, i.e. polymerases. The replication of SARS-CoV-2, the causative agent of the COVID-19 pandemics, is based on the duplication of its RNA genome, an action performed by the viral RNA- dependent-RNA polymerase. In this contribution, for the first time and by using two- dimensional enhanced sampling quantum mechanics/ molecular mechanics, we have determined the chemical mechanisms leading to the inclusion of a nucleotide in the nascent viral RNA strand. We prove the high efficiency of the polymerase, which low- ers the activation free energy to less than 10 kcal/mol. Furthermore, the SARS-CoV-2 polymerase active site is slightly different from those found usually found in other similar enzymes, and particularly it lacks the possibility to enforce a proton shuttle via a nearby histidine. Our simulations show that this absence is partially compensate by lysine, whose proton assist the reaction opening up an alternative, but highly efficient, reactive channel. Our results present the first mechanistic resolution of SARS-CoV-2 genome replication and shed light on unusual enzymatic reactivity paving the way for future rational design of antivirals targeting emerging RNA viruses.
Keywords	covid19
Language	English
Publishing date	2022-02-03
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.02.02.478873
Database	COVID19

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