Elementary Lesions in DNA Subunits: Electron, Hydrogen Atom, Proton, and Hydride Transfers

When DNA is damaged by ionizing radiation, the genes in a cell may acquire mutations or the cell could die. The smallest known DNA-damaging unit is an electron, often low-energy secondary electrons. Additional electrons and transfers involving hydrogen atoms, protons, and hydride anions can damage DNA subunits, including individual nucleobases and nucleoside pairs. Researchers would like to better understand the molecular mechanisms involved in DNA damage from ionizing radiation. In this Account, we highlight our theoretical investigations of the molecular mechanisms of DNA damage using quantum mechanical models. Our investigations use robust theoretical methods with computations conducted in the gas phase and with solution models. We calculate adiabatic electron affinities (AEAs), which describe the energetics of electronic attachment to closed-shell DNA subunits, for the free bases, nucleosides, nucleotides, base pairs, and single and double DNA strand units. Electron affinities for free nucleobases yield the order uracil > thymine > cytosine > guanine > adenine and the same order for the DNA nucleosides, mononucleotides, and nucleoside 3',5'-diphosphates. AEA values increase steadily with the size and complexity of the system because of greater hydration, glycosylation, nucleotide formation, and base pairing. We predict and experimental results partially confirm that most of the more complex and hydrated species are observable as radical anions. Our modeling studies indicate that depyrimidination reactions of radical anion nucleosides release cytosine more often than thymine. Recent experimental results support those findings. Our theoretical studies of DNA base-pair radical anions predict increases in electron affinity accompanying H bonding and solvation. Electron addition facilitates some proton transfers in these pairs, which results in strongly perturbed pairing configurations. Of all nucleobase moieties within the more complex radical anion systems, thymine is best able to retain a negative charge. Charge and spin are well-separated in some of these systems. Radical species derived via hydrogen abstraction from DNA subunits yield large AEA values because they form closed-shell anions. Our studies predict single-strand breaks following H abstraction from nucleotides. Some H-abstraction processes in the DNA base pairs lead to severe distortions in pairing configuration based on our calculations. This body of systematic theoretical studies provides realistic descriptions of some events that lead to elementary DNA lesions, while providing rationalizations for many observed phenomena. Such approaches can lead to the design of new experiments, which would contribute to our understanding of the chemical physics of nucleic acids.