Computational Study of the Changes in the Conformations and Interactions of DNA Subunits Due to the Base Damage Induced by Ionizing Radiation

Abstract

The formation of various DNA base modifications is one of the significant consequences of the action of ionizing radiation on biological systems. These modifications can alter the conformation of damaged fragments and change their interaction with oncoming nucleotides during biosynthesis. In this work, the consequences of the formation of 8-oxo-guanine (OG) and 5-formyl-cytosine (fC) in the DNA structure are considered. The structural and genetic experimental data available in the literature for these modifications is analyzed in comparison to the MM and QM results obtained for the simple fragments of damaged DNA. The computations shed light on how the change in the interaction energy between subunits due to the radiation damage alters their biological function. The existence of OG nucleoside in both anti- and syn- base sugar orientations explains its high mutagenicity. The anti- conformation supports the formation of an OG pair with cytosine, resembling the canonical G:C pair with three hydrogen bonds (H-bonds), while the syn- conformation can form mispairs with purines, both outcomes having the energy and structural characteristics favorable for insertion into the duplex. The H-bonded pair of fC with guanine resembles that of an intact base, and the minor probability of formation of mispairs leads to marginal mutagenicity of fC.

Keywords: 5‐formylcytosine; 8‐oxoguanine; DNA base damage; computer modelling; quantum mechanics.