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Article ; Online: Staring at the Naked Goddess: Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand.

Hognon, Cécilia / Monari, Antonio

2021 Volume 26, Issue 13

Abstract: Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer ... ...

Abstract	Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.
MeSH term(s)	DNA/chemistry ; DNA-Binding Proteins/chemistry ; Endonucleases/chemistry ; Humans ; Models, Chemical
Chemical Substances	DNA-Binding Proteins ; DNA (9007-49-2) ; DCLRE1C protein, human (EC 3.1.-) ; Endonucleases (EC 3.1.-)
Language	English
Publishing date	2021-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26133986
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Article ; Online: Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease.

Hognon, Cécilia / Marazzi, Marco / García-Iriepa, Cristina

International journal of molecular sciences

2022 Volume 23, Issue 10

Abstract: Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ... ...

Abstract	Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys
MeSH term(s)	COVID-19/drug therapy ; Coronavirus Papain-Like Proteases ; Humans ; Ligands ; Papain/metabolism ; Peptide Hydrolases/metabolism ; Protons ; SARS-CoV-2
Chemical Substances	Ligands ; Protons ; Peptide Hydrolases (EC 3.4.-) ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; Papain (EC 3.4.22.2) ; papain-like protease, SARS-CoV-2 (EC 3.4.22.2)
Language	English
Publishing date	2022-05-23
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/ijms23105855
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Article ; Online: Staring at the Naked Goddess

Cécilia Hognon / Antonio Monari

Molecules, Vol 26, Iss 3986, p

Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand

2021 Volume 3986

Abstract	Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.
Keywords	Artemis endonuclease ; DNA lesion repair ; classical molecular dynamics ; quantum mechanics/molecular mechanics ; reaction free energy profiles ; Organic chemistry ; QD241-441
Subject code	612
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Revealing the Molecular Interactions between Human ACE2 and the Receptor Binding Domain of the SARS-CoV-2 Wild-Type, Alpha and Delta Variants.

Hognon, Cécilia / Bignon, Emmanuelle / Monari, Antonio / Marazzi, Marco / Garcia-Iriepa, Cristina

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the ... ...

Abstract	After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in comparison with the wild-type. On one hand, although relevant variations are evidenced, only limited changes in the global stability indicators and in the flexibility profiles have been observed. On the other hand, key differences were obtained by tracking hydrophilic and hydrophobic molecular interactions, concerning both positioning at the ACE2/RBD interface and formation/disruption dynamic behavior.
MeSH term(s)	Humans ; Angiotensin-Converting Enzyme 2/genetics ; SARS-CoV-2/genetics ; COVID-19/genetics ; Machine Learning ; Molecular Dynamics Simulation ; Protein Binding ; Mutation ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-01-28
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/ijms24032517
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Article ; Online: Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease

Cécilia Hognon / Marco Marazzi / Cristina García-Iriepa

International Journal of Molecular Sciences, Vol 23, Iss 5855, p

2022 Volume 5855

Abstract	Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys 111 ), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys 111 deprotonation of the thiol group by a Brønsted–Lowry base; (iii) Cys 111 -S − addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys 111 , that is, prior to the Cys 111 deprotonation. For the second step, MD simulations revealed that His 272 would deprotonate Cys 111 after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys 111 deprotonation, whose equilibrium is largely shifted toward the neutral Cys 111 form. Although thermodynamically disfavored, if Cys 111 is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys 111 -S − negative charge redistribution over the bound ligand, proton transfer from the initially protonated His 272 is favored, finally leading to an irreversibly modified Cys 111 and a restored His 272 . These results elucidate the selectivity ...
Keywords	SARS-CoV-2 ; papain-like protease ; covalent inhibitor ; molecular dynamics ; free energy calculations ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	333
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes.

Hognon, Cecilia / Gebus, Adrien / Barone, Giampaolo / Monari, Antonio

Antioxidants (Basel, Switzerland)

2019 Volume 8, Issue 9

Abstract: By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while ... ...

Abstract	By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.
Language	English
Publishing date	2019-08-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox8090337
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Article: Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

Hognon, Cecilia / Gebus, Adrien / Barone, Giampaolo / Monari, Antonio

Antioxidants. 2019 Aug. 22, v. 8, no. 9

2019

Abstract	By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.
Keywords	DNA ; cations ; electrostatic interactions ; guanine ; humans ; molecular dynamics ; nucleotide sequences ; potassium ; simulation models ; telomeres
Language	English
Dates of publication	2019-0822
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox8090337
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Revealing the Molecular Interactions between Human ACE2 and the Receptor Binding Domain of the SARS-CoV-2 Wild-Type, Alpha and Delta Variants

Cécilia Hognon / Emmanuelle Bignon / Antonio Monari / Marco Marazzi / Cristina Garcia-Iriepa

International Journal of Molecular Sciences, Vol 24, Iss 2517, p

2023 Volume 2517

Abstract: After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the ... ...

Abstract	After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in comparison with the wild-type. On one hand, although relevant variations are evidenced, only limited changes in the global stability indicators and in the flexibility profiles have been observed. On the other hand, key differences were obtained by tracking hydrophilic and hydrophobic molecular interactions, concerning both positioning at the ACE2/RBD interface and formation/disruption dynamic behavior.
Keywords	SARS-CoV-2 ; Alpha variant ; Delta variant ; molecular dynamics ; ACE2/RBD complex formation ; protein-protein interactions ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Never Cared for What They Do: High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage.

Miclot, Tom / Hognon, Cécilia / Bignon, Emmanuelle / Terenzi, Alessio / Grandemange, Stéphanie / Barone, Giampaolo / Monari, Antonio

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 10

Abstract: DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, ...

Abstract	DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.
MeSH term(s)	DNA/radiation effects ; DNA Damage ; DNA Repair ; G-Quadruplexes ; Genomic Instability ; Humans
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-05-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27103256
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Article ; Online: Photoinduced DNA Lesions in Dormant Bacteria: The Peculiar Route Leading to Spore Photoproducts Characterized by Multiscale Molecular Dynamics*.

Francés-Monerris, Antonio / Hognon, Cécilia / Douki, Thierry / Monari, Antonio

Chemistry (Weinheim an der Bergstrasse, Germany)

2020 Volume 26, Issue 62, Page(s) 14236–14241

Abstract: Some bacterial species enter a dormant state in the form of spores to resist to unfavorable external conditions. Spores are resistant to a wide series of stress agents, including UV radiation, and can last for tens to hundreds of years. Due to the ... ...

Abstract	Some bacterial species enter a dormant state in the form of spores to resist to unfavorable external conditions. Spores are resistant to a wide series of stress agents, including UV radiation, and can last for tens to hundreds of years. Due to the suspension of biological functions, such as DNA repair, they accumulate DNA damage upon exposure to UV radiation. Differently from active organisms, the most common DNA photoproducts in spores are not cyclobutane pyrimidine dimers, but rather the so-called spore photoproducts. This noncanonical photochemistry results from the dry state of DNA and its binding to small, acid-soluble proteins that drastically modify the structure and photoreactivity of the nucleic acid. Herein, multiscale molecular dynamics simulations, including extended classical molecular dynamics and quantum mechanics/molecular mechanics based dynamics, are used to elucidate the coupling of electronic and structural factors that lead to this photochemical outcome. In particular, the well-described impact of the peculiar DNA environment found in spores on the favored formation of the spore photoproduct, given the small free energy barrier found for this path, is rationalized. Meanwhile, the specific organization of spore DNA precludes the photochemical path that leads to cyclobutane pyrimidine dimer formation.
MeSH term(s)	DNA/radiation effects ; DNA Damage ; Molecular Dynamics Simulation ; Pyrimidine Dimers/chemistry ; Spores, Bacterial/chemistry ; Ultraviolet Rays
Chemical Substances	Pyrimidine Dimers ; DNA (9007-49-2)
Language	English
Publishing date	2020-09-30
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202002484
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