Computational Studies on the Structure and Mutagenecity of carcinogenic DNA lesions formed for Ochratoxin A and Aristolochic Acids

Abstract

The present thesis uses classical explicit solvent molecular dynamics (MD) simulations to study the mutagenicity of two highly potent carcinogens viz. ochratoxin A (OTA) and aristolochic acid I (AAI). Human exposure to OTA occurs through the consumption of exposed food products, and is linked to a number of toxicological effects, including nephrotoxicity and testicular carcinogenesis. However, exposure to AAI occurs through intake of certain herbal medicines, and has been implicated in chronic renal conditions (aristolochic acid nephropathy) and urothelial carcinoma. The carcinogenic effect of these toxins has been attributed to their ability to form bulky DNA adducts, viz. the C8-linked OT-G, the major adduct formed on exposure to OTA and ALI-N6-A, the most potent adduct formed on exposure to aristolochic acid I. In order to provide molecular level insights and structural basis for mutagenicity, these adducts are site-specifically incorporated into the post-replication DNA duplexes and at the templating position of the trans-lesion synthesis polymerase. Specifically, to understand the propensity of induction of small- deletions (one- and two-base) mutations and predict the preferred base- substitution mutations and the associated post-replication repair-on exposure to these carcinogens. Overall, the present thesis propensity, the OT-G lesion paired opposite a two-base or one-base base bulge or a mismatched base The structural parameters and lesion-site interaction energies of these post-replication DNA duplexes are calculated and analysed to provide insights into the effects of the opposing-base, adduct ionization state and flanking-bases on duplex structural features for the competing adducted DNA conformers, and have been further implicated to repair and mutagenicity associated with OTA exposure.