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

Abstract

Abstract8‐Oxoguanosine is the most common oxidatively generated base damage and pairs with complementary cytidine within duplex DNA. The 8‐oxoguanosine−cytidine lesion, if not recognized and removed, not only leads to G‐to‐T transversion mutations but renders the base pair being more vulnerable to the ionizing radiation and singlet oxygen (1O2) damage. Herein, reaction dynamics of a prototype Watson−Crick base pair [9MOG ⋅ 1MC]⋅+, consisting of 9‐methyl‐8‐oxoguanine radical cation (9MOG⋅+) and 1‐methylcystosine (1MC), was examined using mass spectrometry coupled with electrospray ionization. We first detected base‐pair dissociation in collisions with the Xe gas, which provided insight into intra‐base pair proton transfer of 9MOG⋅+ ⋅ 1MC [9MOG − HN1]⋅ ⋅ [1MC+HN3′]+ and subsequent non‐statistical base‐pair separation. We then measured the reaction of [9MOG ⋅ 1MC]⋅+ with 1O2, revealing the two most probable pathways, C5‐O2 addition and HN7‐abstraction at 9MOG. Reactions were entangled with the two forms of 9MOG radicals and base‐pair structures as well as multi‐configurations between open‐shell radicals and 1O2 (that has a mixed singlet/triplet character). These were disentangled by utilizing approximately spin‐projected density functional theory, coupled‐cluster theory and multi‐referential electronic structure modeling. The work delineated base‐pair structural context effects and determined relative reactivity toward 1O2 as [9MOG − H]⋅>9MOG⋅+>[9MOG − HN1]⋅ ⋅ [1MC+HN3′]+≥9MOG⋅+ ⋅ 1MC.