Modelling radiation-induced damage in the lac operator-lac repressor complex. DNA damage: 8-oxoguanine

Among the DNA lesions induced by ionising radiation, one of the most abunda nt base modifications is that of guanine (G) into 8-oxo-7-hydro-2'-deoxygua nosine (oxoG). The Escherichia coil lac operator-lac repressor complex bear ing one or several oxoG was studied by molecular modelling. The initial str ucture of the complex was obtained from the Protein Data Bank (1CJG entry m odel 1). Systematic replacements of G by oxoG were carried out. Modelling i nvolved energy-minimisation and simulated-annealing techniques using the Am ber force field. Depending on its location along the DNA sequence, oxoG ind uces modifications of the energetic characteristics of the complex, the ele ctrostatic potential distribution on the surfaces of the DNA and of the pro tein, the DNA and protein conformations and DNA and protein flexibility. In the case of the replacement of G by oxoG at position 8 of the fragment, th e most noticeable effects are a 13% decrease in the interaction energy and a 14% reduction in the number of intermolecular hydrogen bonds, all other e ffects being much weaker. Therefore, we may conclude that the presence of o ne or several such base modifications is insufficient to account, alone, fo r the experimental observation of the radiation-induced decrease of Inc ope rator-inc repressor binding extent.