Issue 42, 2019

Probing interaction of a trilysine peptide with DNA underlying formation of guanine–lysine cross-links: insights from molecular dynamics

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.

Graphical abstract: Probing interaction of a trilysine peptide with DNA underlying formation of guanine–lysine cross-links: insights from molecular dynamics

Supplementary files

Article information

Article type
Paper
Submitted
25 Aug 2019
Accepted
08 Oct 2019
First published
10 Oct 2019

Phys. Chem. Chem. Phys., 2019,21, 23418-23424

Probing interaction of a trilysine peptide with DNA underlying formation of guanine–lysine cross-links: insights from molecular dynamics

C. Chan, A. Monari, J. Ravanat and E. Dumont, Phys. Chem. Chem. Phys., 2019, 21, 23418 DOI: 10.1039/C9CP04708E

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