Singlet O-2 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 mecha-nism and the product outcome strongly depend on the nucleobase ionization state and structural context. Previously, exposure of a monomeric 9-methylguanine radical cation (9MG(center dot+), a model guanosine compound) to O-1(2) was found to result in the formation of an 8-peroxide as the initial product. The present work explores the O-1(2) oxidation of 9MG(center dot+) and its dehydrogenated neutral form [9MG - H](center dot) within a Watson-Crick base pair consisting of one-electron-oxidized 9-methylguanine-1-methylcyto sine [9MG center dot 1MC](center dot+). 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 O-1(2) oxidation of both 9MG(center dot+) and [9MG - H](center dot) 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-O-1(2) 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.