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Probing interaction of a trilysine peptide with DNA underlying formation of guanine–lysine cross-links: insights from molecular dynamics
- Source :
- Physical Chemistry Chemical Physics, Physical Chemistry Chemical Physics, Royal Society of Chemistry, 2019, ⟨10.1039/C9CP04708E⟩, Physical Chemistry Chemical Physics, 2019, 21 (42), pp.23418-23424. ⟨10.1039/C9CP04708E⟩, Physical Chemistry Chemical Physics, Royal Society of Chemistry, 2019, 21 (42), pp.23418-23424. ⟨10.1039/c9cp04708e⟩
- Publication Year :
- 2019
- Publisher :
- Royal Society of Chemistry (RSC), 2019.
-
Abstract
- DNA-protein cross-links constitute bulky DNA lesions that interfere with the cellular machinery. Amongst these stable covalently tethered adducts, the efficient nucleophilic addition of the free amino group of lysines onto the guanine radical cation has been evidenced. In vitro addition of a trilysine peptide onto a guanine radical cation generated in a TGT oligonucleotide is so efficient that competitive addition of a water molecule, giving rise to 8-oxo-7,8-dihydroguanine, is not observed. This suggests a spatial proximity between guanine and lysine for the stabilization of the prereactive complex. We report all-atom microsecond scale molecular dynamics simulations that probe the structure and interactions of the trilysine peptide (KKK) with two oligonucleotides. Our simulations reveal a strong, electrostatically driven yet dynamic interaction, spanning several association modes. Furthermore, the presence of neighbouring cytosines has been identified as a factor favoring KKK binding. Relying on ab initio molecular dynamics on a model system constituted of guanine and methylammonium, we also corroborate a mechanistic pathway involving fast deprotonation of the guanine radical cation followed by hydrogen transfer from ammonium leaving as a result a nitrogen reactive species that can subsequently cross-link with guanine. Our study sheds new light on a ubiquitous mechanism for DNA-protein cross-links also stressing out possible sequence dependences.
- Subjects :
- Guanine
Stereochemistry
education
Oligonucleotides
General Physics and Astronomy
Peptide
02 engineering and technology
Molecular Dynamics Simulation
010402 general chemistry
complex mixtures
01 natural sciences
chemistry.chemical_compound
Molecular dynamics
[CHIM]Chemical Sciences
Molecule
Physical and Theoretical Chemistry
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
Binding Sites
[CHIM.ORGA]Chemical Sciences/Organic chemistry
Oligonucleotide
Lysine
021001 nanoscience & nanotechnology
0104 chemical sciences
chemistry
Radical ion
Covalent bond
Quantum Theory
Thermodynamics
bacteria
0210 nano-technology
Oligopeptides
DNA
Subjects
Details
- ISSN :
- 14639084 and 14639076
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Physical Chemistry Chemical Physics
- Accession number :
- edsair.doi.dedup.....d21ddd902587d0a7a9187327d62be70a