Mechanistic insights into photoinduced damage of DNA and RNA nucleobases in the gas phase and in bulk solution

DNA/RNA photohydrates represent a class of well-known biomolecular lesions formed by the absorption of near- to mid-UV light. They are formed via a photoinduced nucleophilic hydrolysis reaction in which water is split (via nucleobase sensitisation) into H + OH radicals. These nascent radicals can then add across C5?C6, saturating the preexisting double bond. If unrepaired, such lesions can lead to mutagenic carcinogenesis, which is responsible for several forms of cancer. Using high-level electronic structure theory (CASPT2), we map the key excited-state reaction paths associated with the reactivity of DNA (guanine and thymine) and RNA (uracil) nucleobases with water. At the outset, we consider the intrinsic reactivity in the isolated gas phase - in which the water (cluster) + chromophore complex is free from environmental perturbations. We then extrapolate the thymine nucleobase to the bulk DNA environment in aqueous solution in order to ascertain the relative importance of hydrate formation in a more complex biological environment. In this latter study we use high-level mixed quantum/classical (QM/MM: CASPT2/AMBER) methods.