Molecular Dynamics Investigation of the Physical Binding of the NNK Diazonium Ion to TP53 exon 5

Abstract

The diazonium ion metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong carcinogen found in tobacco smoke. NNK diazonium ion has been shown to damage DNA through the formation of pyridyloxobutyl (POB) adducts. The current study focuses on the physical interaction of a tumor suppressor gene (TP 53, exon 5) with NNK diazonium ion. TP53 is mutated in nearly 50% of all human tumors and 40% of lung cancer cases. Our work explores the physical interactions that precede bond formation. Density functional theory was used to generate improved force field parameters for the diazonium ion. Molecular dynamics simulations were performed on two systems: NNK diazonium ion and TP53/NNK diazonium ion. Results of the MD simulations that will be presented include an analysis of the various conformations NNK diazonium ion explores and distances of its reactive carbon atoms to reactive atoms of TP53 bases. This will provide insight into the possible reaction mechanism of POB adduct formation.