Molecular dynamics simulations of mismatched DNA duplexes associated with the major C8-linked 2′-deoxyguanosine adduct of the food mutagen ochratoxin A: Influence of opposing base, adduct ionization state and sequence on the structure of damaged DNA

Exposure to ochratoxin A (OTA) is associated with chronic renal diseases and carcinogenesis. The deleterious effects of OTA have been linked to its covalent binding at the C8 position of guanine (G) to form a DNA adduct (OT-G), which causes various mutations. To contribute toward understanding the complex mutagenic profile of OTA, the present work uses a robust computational approach to characterize postreplication DNA structures containing OT-G mismatched with canonical nucleobases. Our MD simulations provide insight into the effects of the opposing base, adduct ionization state, and flanking base on duplex structural features for the competing (major groove (B-type), wedge (W), and stacked (S)) conformers. For the B-type duplexes, our data suggest that significantly more stable lesion-site hydrogen bonding may lead to preferential insertion of an opposing cytosine (C) if the OT moiety is directed toward the major groove at the replication fork. Although the W conformation is consistently predicted to be...