The guanosine nucleoside in DNA is vulnerable to oxidative stress and produces 8-oxo-7,8-dihydroguanosine (OG) lesion. OG may adopt a syn- or anti-conformation, each of which may pair with adenosine and cytidine, respectively, leading to primary and secondary mutations. In this presentation, we report a mass spectrometric study on the model Watson-Crick base-pair radical cation WC-[9MOG-1MC]^●+ consisting of 9-methyl-8-oxoguianie (9MOG) and 1-methylcytosine (1MC). The work focused on base-pair collision-induced dissociation (CID) and its reaction with the lowest electronically excited singlet molecular oxygen. Experiment was carried out in the gas phase by using a guided-ion beam tandem mass spectrometer, which is coupled to an electrospray ionization source for the formation of gaseous WC-[9MOG-1MC]^●+ reactant ions. The measurements included reaction product ions and cross sections as a function of reaction kinetic energy. The experiment was augmented by reaction potential energy surface (PES) exploration using single-reference DFT and CCSD(T) for base-pair CID and multi-reference CASPT2 and NEVPT2 methods for base-pair singlet oxygen oxidation, and followed by kinetics modeling. The WC-[9MOG-1MC]^●+ system, consisting of 9MOG^●+-1MC and its proton-transferred counterpart [9MOG – H]^●-[1MC + H]⁺ in the gas phase, presents non-statistical product branching ratios in collision-induced dissociation, partly due to the entangling of dissociation with intra-base pair proton transfer. Upon attack of [9MOG-1MC]^●+ by singlet oxygen, the initial step corresponds to O₂-addition at the C5 of 9MOG^●+ or [9MOG - H]^●, and the peroxide subsequently abstracts a proton at the N7 of 9MOG. The formation of final products 5OOH-9MOG^●+-1MC and 5OOH-[9MOG – H_N1]^●-[1MC + H_N3_']⁺ have no activation barriers above reactants. The work has demonstrated the application of mass spectrometry in revealing structural context of the 9MOG-1MC base pair and its synergistic damage upon ionization radiation and reactive oxygen species attack. In particular, the 9MOG radical within a WC base pair maintains the same reactivity with singlet oxygen as the isolated single 9MOG^●+, and singlet oxygenation slightly lowers the energies of the proton-transferred base-pair structure in the oxidation products.

Midas I Hsien Tsai

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