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 ( 1 O 2 ). 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 1 O 2 was found to result in the formation of an 8-peroxide as the initial product. The present work explores the 1 O 2 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 1 O 2 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- 1 O 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.