Impact of Radiation Damage on DNA Determined by Computational Simulation

Abstract

Review of molecular dynamics (MD) studies of several radiation-originated lesions on DNA molecules is presented. Main focus is to describe structural and energy changes in DNA molecule with the respect to proper recognition of the lesion by respective repair enzyme. Pyrimidine lesions (cytosinyl radical, thymine glycol) and purine lesion (8-oxoguanine) were subjected to MD simulations for several hundreds picosecond (ps), (200ps for cytosinyl radical, 2 nanosecond for thymine glycol and 8-oxoguanine) using MD simulation code AMBER 5.0 (4.0) and its respective force field modified for each lesion. Simulations were performed as all atoms simulations for fully solvated solute molecules in water. Negative charges of DNA phosphates were neutralized by sodium counterions Na+ that are essential for its double helical structure. In most cases the significant structural changes in DNA are observed: a) breaking of hydrogen bonds network between complementary bases and resulting opening of the double helix (cytosinyl radical, 8-oxoguanine); b) sharp bending of the DNA helix centered at the lesion site (thymine glycol); and c) flipped-out base (8-oxoguanine). These changes are related to overall collapsing of the double helical structure around the lesion and are considered to facilitate docking of the repair enzyme into the DNA and formation of DNA-enzyme complex. Stable DNA-enzyme complex is necessary condition for the onset of entire enzymatic repair process. In addition to the structural changes, specific values of electrostatic interaction energy are detected at several lesion sites (thymine glycol, 8-oxoguanine). The specific electrostatic energy is considered as a factor that enables repair enzyme to discriminate lesion from native, non-damaged site.