title: Singlet Oxygen Attack on Guanine: Reactivity and Structural Signature within the B-DNA Helix.
abstract: Oxidatively generated DNA lesions are numerous and versatile, and have been the subject of intensive research since the discovery of 8-oxoguanine in 1984. Even for this prototypical lesion, the precise mechanism of formation remains elusive due to the inherent difficulties in characterizing high-energy intermediates. We have probed the stability of the guanine endoperoxide in B-DNA as a key intermediate and determined a unique activation free energy of around 6 kcal mol(-1) for the formation of the first C-O covalent bond upon the attack of singlet molecular oxygen ((1) O2 ) on the central guanine of a solvated 13 base-pair poly(dG-dC), described by means of quantum mechanics/molecular mechanics (QM/MM) simulations. The B-helix remains stable upon oxidation in spite of the bulky character of the guanine endoperoxide. Our modeling study has revealed the nature of the versatile (1) O2 attack in terms of free energy and shows a sensitivity to electrostatics and solvation as it involves a charge-separated intermediate.
authors.affiliation: Univ.Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Laboratoire de Chimie, 69342, Lyon, France. elise.dumont@ens-lyon.fr.
authors.forename: Elise
authors.identifier: http://orcid.org/0000-0002-2359-111X
authors.initials: E
authors.lastname: Dumont
authors.affiliation: Univ.Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Laboratoire de Chimie, 69342, Lyon, France.
authors.forename: Raymond
authors.initials: R
authors.lastname: Grüber
authors.affiliation: Univ.Lyon, Ens de Lyon, CNRS UMR 5182, Université Claude Bernard Lyon 1, Laboratoire de Chimie, 69342, Lyon, France.|Univ. Lyon, CNRS, Université Claude Bernard Lyon 1, Ens de Lyon, Institut des sciences analytiques, UMR 5280, 5 rue de la Doua, 69100, Villeurbanne, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bignon
authors.affiliation: Univ. Lyon, CNRS, Université Claude Bernard Lyon 1, Ens de Lyon, Institut des sciences analytiques, UMR 5280, 5 rue de la Doua, 69100, Villeurbanne, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morell
authors.affiliation: Departament Quimica Fisica, Universidad de València, 46100, Burjassot, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Aranda
authors.affiliation: CEA and Université Grenoble Alpes, INAC-SyMMES, 38000, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ravanat
authors.affiliation: Departament Quimica Fisica, Universidad de València, 46100, Burjassot, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Tuñón
mesh_terms: D020029:Base Pairing; D059371:DNA, B-Form / Q000737:chemistry* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011089:Polydeoxyribonucleotides / Q000737:chemistry*; D026082:Singlet Oxygen / Q000737:chemistry*
chemical_list: D059371:DNA, B-Form; D011089:Polydeoxyribonucleotides; D026082:Singlet Oxygen; C019530:poly(dC-dG); C024829:8-hydroxyguanine; D006147:Guanine
keywords: DNA; DNA damage; DNA structure; molecular dynamics; molecular modeling; singlet oxygen