Singlet O₂ Oxidation of the Radical Cation versus the Dehydrogenated Neutral Radical of 9-Methylguanine in a Watson–Crick Base Pair. Consequences of Structural Context

Abstract

In DNA, guanine is the most susceptible to oxidative damage by exogenously and endogenously produced electronically excited singlet oxygen (1O2). The reaction mechanism and the product outcome strongly depend on the nucleobase ionization state and structural context. Previously, exposure of a monomeric 9-methylguanine radical cation (9MG•+, a model guanosine compound) to 1O2 was found to result in the formation of an 8-peroxide as the initial product. The present work explores the 1O2 oxidation of 9MG•+ and its dehydrogenated neutral form [9MG – H]• within a Watson–Crick base pair consisting of one-electron-oxidized 9-methylguanine–1-methylcytosine [9MG·1MC]•+. Emphasis is placed on entangling the base pair structural context and intra-base pair proton transfer with and consequences thereof on the singlet oxygenation of guanine radical species. Electrospray ionization coupled with guided-ion beam tandem mass spectrometry was used to study the formation and reaction of guanine radical species in the gas phase. The 1O2 oxidation of both 9MG•+ and [9MG – H]• is exothermic and proceeds barrierlessly either in an isolated monomer or within a base pair. Single- and multi-referential theories were tested for treating spin contaminations and multi-configurations occurring in radical–1O2 interactions, and reaction potential energy surfaces were mapped out to support experimental findings. The work provides a comprehensive profile for the singlet oxygenation of guanine radicals in different charge states and in the absence and the presence of base pairing. All results point to an 8-peroxide as the major oxidation product in the experiment, and the oxidation becomes slightly more favorable in a neutral radical form. On the basis of a variety of reaction pathways and product profiles observed in the present and previous studies, the interplay between guanine structure, base pairing, and singlet oxygenation and its biological implications are discussed.

Effects of Intra‐Base Pair Proton Transfer on Dissociation and Singlet Oxygenation of 9‐Methyl‐8‐Oxoguanine−1‐Methyl‐Cytosine Base‐Pair Radical Cations

“…For comparison, the experimental 1 O 2 excitation energy is 0.98 eV [59a] . Furthermore, in our previous study on the 1 O 2 reactions with monohydrated 9‐methylguanine radical cation [46] and monohydrated 9‐methylguanine−1‐methylcytosine base‐pair radical cation, [41c] the CASPT2 method was able to quantitatively reproduce their experimentally measured reaction exothermicity.…”