Role of structural and energetic factors in regulating repair of a bulky DNA lesion with different opposite partner bases.

Extensive molecular modeling with molecular dynamics simulations and van der Waals energy analyses were used to elucidate the striking finding that a mutagenic benzo[a]pyrene-derived DNA lesion, the base-displaced intercalated 10R-(+)-cis-anti-B[a]P-N(2)-dG (G*), manifests large differences in nucleotide excision repair (NER) efficiencies in DNA duplexes, which depend on the identities of the partner base opposite G*. The nature of the partner base causes marked differences in the extent of its major groove extrusion and dynamics, as well as energetic stability of the intercalation pocket that parallels the relative NER efficiencies.