Conformational analysis of DNA damaged by aristolochic acids to assess the toxicity and repair : a computational study

Abstract

Molecular modeling study is carried out on DNA damaged by aristolochic acids I and II. The carcinogenic effects of these acids have been attributed to the formation of bulky adducts within DNA (specifically with the adenine and guanine nucleobases). The analysis is initiated by considering the conformational preferences of the aristolochic acid adducts in small models (nucleobase, nucleoside and nucleotide) using quantum mechanical calculations. Subsequently, the adducts were studied using molecular dynamics simulations at the oligonucleotide level by incorporating the damaged base in an 11-mer DNA strand. The structural preferences of adenine and guanine adducts are compared, which may explain the experimentally-observed differential repair propensity. Finally, sequence-induced differences in the structural features of adducted DNA containing the ALI-adenine lesion are analyzed to explain the experimentally-reported higher mutagenicity of the lesion in a particular sequence. Results and implications from each of these studies are presented, and future research directions are proposed.