H. Nikjoo

Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events

Modelling and calculations are presented as a first step towards mechanistic interpretation and prediction of radiation effects based on the spectrum of initial DNA damage produced by low energy electrons (100 eV-4.5 keV) that can be compared with experimental information. Relative yields of single and clustered strand breaks are presented in terms of complexity and source of damage, either by direct energy deposition or by reaction of OH radicals, and dependence on the activation probability of OH radicals and the amount of energy required to give a single strand break (ssb). Data show that the majority of interactions in DNA do not lead to damage in the form of strand breaks and when they do occur, they are most frequently simple ssb. However, for double-strand breaks (dsb), a high proportion (approximately 30%) are of more complex forms, even without considering additional complexity from base damage. The greater contribution is from direct interactions in the DNA but reactions of OH radicals add substantially to this, both in terms of the total number of breaks and in increasing the complexity within a cluster. It has been shown that the lengths of damaged segments of DNA from individual electron tracks tend to be short, indicating that consequent deletion length (simply by loss of a fragment between nearby dsb) would be short, very seldom exceeding a few tens of base pairs.

Track Structure Analysis of Ultrasoft X-rays Compared to High- and Low-LET Radiations

Monte-Carlo track structure simulations of ultrasoft X-rays, and of selected low- and high-LET radiations for comparison, have been used to obtain statistically valid frequency distributions of energy deposition in small subcellular targets which resemble the dimensions of short segments of DNA, nucleosomes and short segments of chromatin fibre. It is found that in all cases large numbers (approximately 10(3] of direct energy deposition events occur in these targets in a single mammalian cell irradiated with 1 Gy of any of these radiations. In almost all cases the numbers of energy depositions of substantial size (say, approximately greater than 100 eV in a DNA segment, approximately greater than 300 eV in a nucleosome or approximately greater than 800 eV in a segment of chromatin fibre) are also quite large, being approximately 10 to 100 per cell per Gy. It seems clear therefore that the direct effects of radiation on macromolecules must be considered in assessing the biological effects of any ionizing radiations on mammalian cells. The calculations also show that high-LET radiations can produce uniquely large energy depositions in the targets, such as are virtually unachievable by any of the other radiations; this allows the possibility of unique biochemical and cellular damage by high-LET radiations. At any realistic dose for mammalian cells, virtually all the energy depositions in these targets, from all the radiations, are due to single independent tracks; the multi-track component is negligibly small. The absolute numbers of energy depositions of approximately greater than 100 eV in DNA segments in a cell are similar to experimentally measured numbers of DNA double-strand breaks, but both these sets of numbers are one or two orders of magnitude larger than the numbers of lethal events produced in mammalian cells. The frequency of threshold energy of approximately 120 eV in a DNA segment correlates reasonably well with the relative biological effectiveness of ultrasoft X-rays and low-LET radiations for relatively radioresistant cells, but a lower threshold energy may be required for other, more sensitive, cells.

Model for Radial Dependence of Frequency Distributions for Energy Imparted in Nanometer Volumes from HZE Particles

Abstract Cucinotta, F. A., Nikjoo, H. and Goodhead, D. T. Model for Radial Dependence of Frequency Distributions for Energy Imparted in Nanometer Volumes from HZE Particles. This paper develops a deterministic model of frequency distributions for energy imparted (total energy deposition) in small volumes similar to DNA molecules from high-energy ions of interest for space radiation protection and cancer therapy. Frequency distributions for energy imparted are useful for considering radiation quality and for modeling biological damage produced by ionizing radiation. For high-energy ions, secondary electron (δ-ray) tracks originating from a primary ion track make dominant contributions to energy deposition events in small volumes. Our method uses the distribution of electrons produced about an ions path and incorporates results from Monte Carlo simulation of electron tracks to predict frequency distributions for ions, including their dependence on radial distance. The contribution from primary ion events is treated using an impact parameter formalism of spatially restricted linear energy transfer (LET) and energy-transfer straggling. We validate our model by comparing it directly to results from Monte Carlo simulations for proton and α-particle tracks. We show for the first time frequency distributions of energy imparted in DNA structures by several high-energy ions such as cosmic-ray iron ions. Our comparison with results from Monte Carlo simulations at low energies indicates the accuracy of the method.

Cross-sections for water vapour for the Monte Carlo electron track structure code from 10 eV to the MeV region

Electron cross-sections were summarized for an accurate simulation of the track structure of high energy electrons up to a few MeV in water vapour. Elastic scattering was described by the Rutherford formula taking the screening effect into account. Partial and total ionization cross-sections were calculated using Seltzers formula based on the Weizsacker-Williams method. The total excitation cross-section was evaluated by a so-called Fano plot with parameters given by Berger and Wang. The validity of the cross-sections was examined by comparison with experimental and calculated data. Use of these cross-sections enabled the development of a Monte Carlo track structure code KURBUC encompassing the energy range between 10 eV and 10 MeV. Finally the tracks generated by KURBUC were compared with those generated by MOCA8B in terms of radial distributions of interactions, point kernel and frequencies of energy deposition in small cylindrical targets pertaining to biological macromolecules such as DNA.

Comparison and assessment of electron cross sections for Monte Carlo track structure codes.

The purpose of this study was to make an intercomparison and assessment of cross sections for electrons in water used in electron track structure codes. This study is intended to shed light on the extent to which the differences between the input data and physical and chemical assumptions influence the outcome in biophysical modeling of radiation effects. Ionization cross sections and spectra of secondary electrons were calculated by various theories. The analyses were carried out for water vapor cross sections, as these are more abundant and readily available. All suitable published experimental total ionization cross sections were fitted by an appropriate function and used for generation of electron tracks. Three sets of compiled data were used for comparison of total excitation cross sections and mean excitation energy. The tracks generated by a Monte Carlo track code, using various combinations of cross sections, were compared in terms of radial distributions of interactions and point kernels. The spectrum of secondary electrons emitted by the ionization process was found to be the factor that has the most influence on these quantities. A different set of cross sections for excitation and elastic scattering did not affect the electron track structure as much as did ionization cross sections. It is concluded that all codes, using different cross sections and in different phase, currently used for biophysical modeling exhibit close similarities for energy deposition in larger size targets while appreciable differences are observed in B-DNA-size targets. We recommend fitted functions to all available suitable experimental data for the total ionization and elastic cross sections. We conclude that most codes produce tracks in reasonable agreement with the macroscopic quantities such as total stopping power and total yield of strand breaks. However, we predict differences in frequencies of clustering in tracks from the different models.

Energy Deposition in Small Cylindrical Targets by Monoenergetic Electrons

Calculations of energy deposition in cylindrical target volumes of diameter and height 1-100 nm, including those similar to the dimensions of biological molecules and structures such as DNA, nucleosomes and chromatin fibre, have been made. The calculations used the Monte Carlo track structure program MOCA8B for electrons of initial energy 0.1-100 keV. Details of the calculation are presented, as well as a selection of results. The frequency distributions of energy deposition events per gray per target, placed at random in a homogeneous aqueous medium, are given for uniform irradiation with monoenergetic electrons of various energies. The frequency distributions have been used to predict the initial biophysical parameters such as relative effectiveness for initial damage. These suggest that the final biological effects which depend on complex local damage may show substantial variations in biological effectiveness for different low linear energy transfer radiations, whereas those that depend on simple local damage may not.

Energy deposition in small cylindrical targets by ultrasoft x-rays

A Monte Carlo technique has been employed to calculate the energy deposition events in small cylindrical targets (less than or equal to 100 nm), including sizes which represent the DNA duplex, nucleosome and chromatin fibre, by simulated electron tracks from C (278 eV), A1 (1487 eV) and Ti (4509 eV) characteristic ultrasoft x-rays in water. Detailed examples of input data tables for the generation of electron tracks produced from the x-ray photon interactions are presented. Frequencies of energy deposition events per gray for target sizes from 1 to 100 nm are given and comparisons have been made with radiations of different qualities.

Kinetics of DSB rejoining and formation of simple chromosome exchange aberrations

PURPOSE To investigate the role of kinetics in the processing of DNA double strand breaks (DSB), and the formation of simple chromosome exchange aberrations following X-ray exposures to mammalian cells based on an enzymatic approach. METHODS Using computer simulations based on a biochemical approach, rate-equations that describe the processing of DSB through the formation of a DNA-enzyme complex were formulated. A second model that allows for competition between two processing pathways was also formulated. The formation of simple exchange aberrations was modelled as misrepair during the recombination of single DSB with undamaged DNA. Non-linear coupled differential equations corresponding to biochemical pathways were solved numerically by fitting to experimental data. RESULTS When mediated by a DSB repair enzyme complex, the processing of single DSB showed a complex behaviour that gives the appearance of fast and slow components of rejoining. This is due to the time-delay caused by the action time of enzymes in biomolecular reactions. It is shown that the kinetic- and dose-responses of simple chromosome exchange aberrations are well described by a recombination model of DSB interacting with undamaged DNA when aberration formation increases with linear dose-dependence. Competition between two or more recombination processes is shown to lead to the formation of simple exchange aberrations with a dose-dependence similar to that of a linear quadratic model. CONCLUSIONS Using a minimal number of assumptions, the kinetics and dose response observed experimentally for DSB rejoining and the formation of simple chromosome exchange aberrations are shown to be consistent with kinetic models based on enzymatic reaction approaches. A non-linear dose response for simple exchange aberrations is possible in a model of recombination of DNA containing a DSB with undamaged DNA when two or more pathways compete for DSB repair.Purpose : To investigate the role of kinetics in the processing of DNA double strand breaks (DSB), and the formation of simple chromosome exchange aberrations following X-ray exposures to mammalian cells based on an enzymatic approach. Methods : Using computer simulations based on a biochemical approach, rate-equations that describe the processing of DSB through the formation of a DNA-enzyme complex were formulated. A second model that allows for competition between two processing pathways was also formulated. The formation of simple exchange aberrations was modelled as misrepair during the recombination of single DSB with undamaged DNA. Non-linear coupled differential equations corresponding to biochemical pathways were solved numerically by fitting to experimental data. Results : When mediated by a DSB-repair enzyme complex, the processing of single DSB showed a complex behaviour that gives the appearance of fast and slow components of rejoining. This is due to the time-delay caused by the action time of enzymes in biomolecular reactions. It is shown that the kinetic- and dose- responses of simple chromosome exchange aberrations are well described by a recombination model of DSB interacting with undamaged DNA when aberration formation increases with linear dose-dependence. Competition between two or more recombination processes is shown to lead to the formation of simple exchange aberrations with a dose-dependence similar to that of a linear-quadratic model. Conclusions : Using a minimal number of assumptions, the kinetics and dose-response observed experimentally for DSB rejoining and the formation of simple chromosome exchange aberrations are shown to be consistent with kinetic models based on enzymatic reaction approaches. A non-linear dose-response for simple exchange aberrations is possible in a model of recombination of DNA containing a DSB with undamaged DNA when two or more pathways compete for DSB repair.

Development of a Monte Carlo track structure code for low-energy protons in water

Purpose : The development of a new generation of Monte Carlo track structure code is described, which simulates full slowing down of low-energy proton history tracks (lephist) in the range 1 keV-1 MeV in water. Material and methods : All primary protons are followed down to 1 keV and all electrons to 1 eV. All primary interactions, including elastic scattering, ionization, excitation and charge exchange processes by protons and neutral hydrogen were taken into account. Cross-sections for proton and hydrogen impact were obtained from experimental data for water. Where data were lacking, the existing experimental data were fitted and extrapolated. The tracks of secondary electrons were generated using the electron track code kurbuc. The cross-sections and the energy transfer data were individually evaluated for the principal interactions induced by protons and hydrogen atoms in water. The analysis starts with the published cross-section data for water using a semi-empirical model including contributions from the neutral hydrogen atoms. For excitation cross-sections, the original Miller-Green analytical formula was used. For ionization by neutral hydrogen atoms, the same energy spectrum was assumed for secondary electrons as for protons. The total cross-sections were taken from the experiment of Blorizadeh and Rudd (1986b, c). For the stripping of charge by neutral hydrogen the data of Toburen et al. (1968) were used. Results : Data are presented on total and differential elastic crosssections as a function of energy and scattering angle respectively; single and double differential cross-sections for secondary electrons ejected by various energy proton impact; total cross-sections due to proton and hydrogen impact on water; stopping power cross-sections; and fraction of stopping power for water for protons as a functions of proton energy. Conclusions : Tracks were analysed to provide confirmation on the reliability of the code and information on physical quantities, such as range, W, restricted stopping power, radial dose profiles and some microdosimetric parameters. Model calculations show good agreement with the experimental and calculated data.

Yields of SSB and DSB induced in DNA by Al K ultrasoft X-rays and α-particles: comparison of experimental and simulated yields

Purpose : To compare experimental yields of single strand breaks (SSB) and double strand breaks (DSB) induced in plasmid DNA in aqueous solution by f -particles and Al K ultrasoft X-rays (USX) with the corresponding yields, generated via computer simulations, for a range of mean diffusion distances of the hydroxyl radical (OH). Materials and methods : Aerobic, aqueous solutions of plasmid DNA were irradiated at 277K with 238 Pu f -particles or USX in the presence of 10 -4 to 0.33 mol dm -3 Tris and the yields of SSB and DSB determined by gel electrophoresis. Computer simulations, using Monte Carlo track-structure codes for 1.5keV electrons (CPA100) and 3.2MeV f -particle track segments (PITS), were used to obtain yields of DNA SSB and DSB at different OH scavenger conditions. Results : The experimental yield of SSB and DSB induced by AlK USX and SSB induced by f -particles and the dependences on the mean diffusion distance of the OH are in reasonable agreement with the corresponding simulated yields and their corresponding dependences. However, for DSB induced by f -particles, a significant systematic difference exists between the simulated and experimental yields over the full OH scavenging range, with the simulated yields being a factor of two to three greater than the experimental values. Conclusion : That the simulated yields of strand breaks are generally in reasonable agreement with those determined experimentally over a wide range of OH scavenging capacities, increases confidence in the use of these simulations as a valuable source of quantitative, mechanistic information on DNA damage induced at very low radiation doses.