Monte Carlo Simulation of DNA Damage by Low Let Radiation using Inhomogeneous Higher Order DNA Targets.

To test possible effects of the heterogeneous nature of the cell nucleus on simulation results of radiation-induced DNA damage. inhomogeneous targets have been implemented in the biophysical code PARTRAC. The geometry of the DNA and the histones was defined by spheres around the constituent atoms, Electron cross sections in liquid water were scaled according to the mass density of the different materials. whereas photon cross sections were derived from the sum of the cross section, for the constituent atoms. In the case of higher energy electrons the simulations show an increase of energy deposition in the DNA proportional to its high mass density. For photons with energies in the range of the carbon and the oxygen K-shell (0.28-0.53 keV), cross sections of DNA are larger than those of water. leading to an increased yield of strand breaks per average absorbed dose in the cell nucleus

Simulation of DNA Damage after Proton and Low Let Irradiation.

A module for proton track structure simulation in liquid water was implemented in the biophysical model PARTRAC. Simulated tracks of energy deposition events from the radiation under investigation were superimposed on a higher-order DNA target model describing the whole genome inside a human cell. The parameters controlling DNA damage from direct and indirect effects were adapted to agree with yields and pathway contributions derived from gamma ray irradiation experiments. Single and double strand break (DSB) induction Was Simulated for irradiations by protons, photon, and electrons over a wide range of initial energies. The relative biological effectiveness for DSB induction after proton irradiation was found to rise from 1.2 at 5 keV mum(-1) to about 2.5 at 70 keV.mum(-1). About half of this grown resulted from an increased production of DSB clusters associated with Small (< 10 kbp) fragments

Simulation of DNA fragment distributions after irradiation with photons

The Monte Carlo track structure code PAR-TRAC has been further improved by implementing electron scattering cross-sections for liquid water and by explicitly modelling the interaction of water radicals with DNA. The model of the genome inside a human cell nucleus in its interphase is based on the atomic coordinates of the DNA double helix with an additional volume for the water shell. The DNA helix is wound around histone complexes, and these nucleosomes are folded into chromatin fibres and further to fibre loops, which are interconnected to build chromosomes with a territorial organisation. Simulations have been performed for the irradiation of human fibroblast cells with carbon K and aluminium K ultrasoft x-rays, 220 kVp x-rays and Co-60 gamma-rays. The ratio single-strand breaks to double-strand breaks (ssb/dsb) for both types of ultrasoft x-rays is lower than for gamma-rays by a factor of 2. The contributions of direct and indirect effects to strand break induction are almost independent of photon energy. Strand break patterns from indirect effects reflect differences in the susceptibility of the DNA helix to OH. attack inside the chromatin fibre. Distributions of small DNA fragments (<3 kbp) are determined by the chromatin fibre structure irrespective of whether direct or indirect effects are causing the breaks. In the calculated fragment size distributions for larger DNA fragments (>30 kbp), a substantial deviation from random breakage is found only for carbon K irradiation, and is attributed to its inhomogeneous dose distribution inside the cell nucleus. For the other radiation qualities, the results for larger fragments can be approximated by random breakage distributions calculated for a yield of dsb which is about 10% lower than the average for the whole genome. The excess of DNA fragments detected experimentally in the 8-300 kbp region after x-ray irradiation is not seen in our simulation results

Simulation of 125I induced DNA strand breaks in a CAP-DNA complex.

The E. coli catabolite gene activator protein (CAP)-DNA complex with I-125 located at the position of the H5 atom of the cytosine near the centre was incorporated into the PARTRAC track structure code. DNA strand breaks due to irradiation were calculated by track structure and radical attack simulations strand breaks due to neutralisation of the highly charged Te-125 ion were derived from a semi-empirical distribution. According to the calculations, the neutralisation effect dominates the strand breakage frequency at 2 bases away front the I-125 decay site on both strands. The first breakage distribution counted from a P-32 labelled end on the strand with I-125 agreed well with experimental data. but on the opposite strand. the calculated distribution is more concentrated around the decay site and its yield is about 20% larger than the measured data