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

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.