Physical Binding of a Tobacco-Specific Carcinogen (NNK) Metabolite to the Human TP53 Gene with Ramifications for DNA Damage and Mutations

Abstract

The most prevalent and carcinogenic of the tobacco-specific nitrosamines is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK is a potent carcinogen that causes numerous types of cancers, most commonly lung adenomas and adenocarcinomas. The diazonium ion formed through the enzymatic metabolism of NNK by cytochrome P450s, can bind chemically to DNA (DNA damage). These adducts, if not repaired, can cause mutations that lead to tumorigenesis. We do not have a complete understanding of the binding of the diazonium ion to DNA which is important for future preventative strategies of NNK-associated cancers. The focus of this research is to computationally model and understand the physical interactions between the NNK diazonium ion and exon 5 of the human TP53 gene. We used a Lamarckian genetic algorithm to minimize a physics-based free energy function that allows us to estimate the free energy differences between the NNK diazonium ion along with TP53 in an unbound state and when they are physically bound. The free energy function employs pair-wise terms that evaluate dispersion, Pauli repulsions, hydrogen bonding, electrostatics and desolvation, along with a term for the lost conformational energy when the molecules bind. We will present the most probable NNK diazonium ion-TP53 physical binding sites and discuss how DNA damage (pyridyloxobutylated adducts in particular) may be occurring when it is exposed to this tobacco-specific carcinogen.