The Elusive Noncanonical Isomers of Ionized 9-Methyladenine and 2′-Deoxyadenosine

Abstract

Noncanonical nucleobases and nucleosides represent newly discovered species of relevance for DNA ionization. We report a targeted synthesis of gas-phase 9-methylene(1H)adenine cation radical (2 +• ) as a low-energy isomer of ionized 9methyladenine. Ion 2 +• showed unique collision-induced dissociation and UV−vis photodissociation action spectra that distinguished it from other cation radical isomers. Ab initio energy calculations with coupled cluster theory extrapolated to the complete basis set limit, CCSD(T)/CBS, identified cation radical 2 +• as the global energy minimum of the adenine-related C 6 H 7 N 5 +• isomers. The action spectrum of 2 +• was assigned on the basis of vibronic absorption spectra that were calculated with timedependent density functional theory for multiple vibrational configurations of thermal ions. The major dissociation of 2 +• proceeded by hydrogen loss that was elucidated by deuterium labeling at the exchangeable N-1 and NH 2 positions and C-8 position and by kinetic analysis. The dissociation involved a reversible rearrangement to intermediate dihydropteridine structures, yielding a protonated aminopteridine as the product, which was identified by multistep UV−vis action spectroscopy. We also report a computational study of related noncanonical isomers of 2′-deoxyadenosine cation radical having the radical defect at C-1′ that were found to be thermodynamically more stable than the canonical isomer in both the gas phase and aqueous solution. The noncanonical isomers were calculated to have extremely low ion−electron recombination energies of 4.42−5.10 eV that would make them dead-end hole traps if produced by DNA ionization.

Noncanonical Isomers of Nucleoside Cation Radicals: An Ab Initio Study of the Dark Matter of DNA Ionization

“…Ab initio calculations at the CCSD­(T)/ complete basis set (CBS) level of theory have indicated that the noncanonical 2-OH methylenecytosine cation radical and its N3-H-tautomer were 59 and 56 kJ mol –1 more stable, respectively, than the canonical form . The noncanonical isomer of the 9-methyladenine cation radical, [9-methylene-( 1H )­adenine] + · , has been generated recently in the gas phase and calculated to be more stable than its canonical isomer . The [9-methylene-( 1H )­adenine] + · ion has been shown to have a distonic electronic structure, whereby the radical and charge sites resided at different atoms .…”

Flying DNA Cation Radicals in the Gas Phase: Generation and Action Spectroscopy of Canonical and Noncanonical Nucleobase Forms

“…The power of gas-phase ion chemistry in generating unusual DNA-related cation radicals can be illustrated by the targeted synthesis of ionized 9-methylene-(1 H ) adenine, which is the lowest-energy noncanonical isomer of 9-methyladenine cation radical (Figure ). The noncanonical isomer was found to have a distinct UV–visPD action spectrum (Figure a) that substantially differed from that of the canonical isomer (Figure b). The isomers also differed in the nature of electronic excitations giving rise to the absorption bands in the action spectra.…”

“…UV–visPD action spectra of (a) 9-methylene-(1 H )­adenine and (b) 9-methyladenine cation radicals. Adapted in part from ref . Copyright 2021 American Chemical Society.…”

“…The existence of noncanonical nucleobase cation radicals and their facile formation upon electron-transfer oxidation in metal complexes raises the question of the role such noncanonical structures can play in DNA ionization. Consider that noncanonical cation radicals are more stable than their canonical isomers and have very low ion–electron recombination energies, for example, RE ad = 4.42 eV for the lowest-Gibbs-energy conformer of (2′-deoxyribos-1-yl-(1 H )­adenine) +• to be compared with RE ad = 7.82 eV for the canonical 2′-deoxyadenosine cation radical . Hence the noncanonical forms may be expected to also have very low redox-potentials in aqueous solution to function as hole traps in DNA ionization.…”

“…Consider that noncanonical cation radicals are more stable than their canonical isomers and have very low ion−electron recombination energies, for example, RE ad = 4.42 eV for the lowest-Gibbsenergy conformer of (2′-deoxyribos-1-yl-(1H)adenine) +• to be compared with RE ad = 7.82 eV for the canonical 2′deoxyadenosine cation radical. 40 Hence the noncanonical condensed-phase studies with suitable oligonucleotide models to determine if noncanonical forms can be produced in a reactive solvent environment and explore their structure and reactions.…”