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Computer modeling of radiation effects

Computer modeling of radiation effects . 20th International CODATA Conference 25 October 2006, Beijing. Noriyuki B. Ouchi and Kimiaki Saito Radiation Effects Analysis Research Group, Nuclear Science and Engineering Directorate, J apan A tomic E nergy A gency. Table of Contents.

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Computer modeling of radiation effects

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  1. Computer modeling of radiation effects 20th International CODATA Conference 25 October 2006, Beijing Noriyuki B. Ouchi and Kimiaki Saito Radiation Effects Analysis Research Group, Nuclear Science and Engineering Directorate, Japan Atomic Energy Agency

  2. Table of Contents • Introduction • Simulation of DNA strand breaks by ionizing radiation • Molecular dynamical study of the DNA lesion repair • Modeling and simulation of the cellular level tumorigenesis • Conclusion

  3. High Dose effect 1. Introduction • Radiation Effects ? • Deterministic effect -- organ/tissue damage (or death) • Late time (stochastic) effect -- radiation induced cancer • Low dose radiation risk • risk = probability of cancer incidence At low dose region, quantitative risk estimation are not so easily obtained.

  4. Dose-Response Assessment by extrapolation Cancer incidence Low dose Dose Risk estimation at low dose radiation needs further study based on the Biological mechanisms.

  5. Scale of the++ Tumorigenesis cm mm (10-3) μm (10-6) nm (10-9) Å (10-10) Cellular level simulation Carcinogenesis Initial process of the DNA damage Gene-mutation DNA Repair DNA damage Radical reactions Basis of risk estimation DNA lesion repair ionization 10-15s 10-9s 10-6s sec. min. hour day year

  6. 2. Initial process of radiation induced DNA Damage To clarify the relations between track structure and DNA strand breaks. Single Strand Break (SSB) Double Strand Break (DSB) Radiation to the cell nucleus causes damage to DNA Biologically important damage Question: What kind of radiation with what type of track generate how much damages ?

  7. Simulation method Track structure Radical production Radical diffusion Target DNA modeling • Track structure calculation • Radical production • DNA modeling • Calculating DNA and radical reactions Track structure: spatial distribution of energy deposition of ionizing radiation

  8. Simulation example DNA damage induction simulation (proton + solenoid DNA)

  9. Result [SSB/DSB ratio] Indicator of complexity of DNA damage 60Co 10keV proton photon α 1MeV 135keV 344keV linear model nucleosome model LET [Linear Energy Transfer] - energy deposition by the charged particle per unit path length 1MeV DSB yield increasing with LET up to 100 keV/m

  10. 3. Molecular dynamical study of the DNA lesion repair Position of each atoms (i) Initial condition (configuration) O mass H Force acting on atom i H Potential energy of the system Molecular Dynamics simulation To clarify a dependency between damaged DNA structural change and capability of the DNA repair.

  11. Simulation example

  12. Shape change of damaged DNA 1.3 ns AP site 8-oxoG Clustered damage Damaged DNA: 8oxo-G + AP site Native DNA (no damage) 2.0 ns • Damaged DNA shows bending movement at leisioned site • Dynamic analysis of DNA structure is ongoing.

  13. 3. Modeling and simulation of the cellular level tumorigenesis The dynamics of the carcinogenesis is studied by the simulation of the cell group in the cell level. • Same configuration with Cell culture system • Can study colony formation or tumorigenesis. • Can introduce dynamical based group effect • Easily comparable with the experiments. • Molecular biologically based model.

  14. Intracellular dynamics Cell transformation τ4 τ1 τ2 τ3 Ppm PC PI kd1 kd2 kd3 kd4 kd:Prob. of cell death PI, Ppm, Pc: prob. of cell state change (genetic) cell statet : normal, initiation, promotion, cancer Cell division If a(s) > ac then cell division occur

  15. Details of the model (J1,a1,l1) τ τ τ τ １ 2 3 4 (J2,a2,l2) (J3,a3,l3) (J4,a4,l4) Intracellular state change affects the physical parameters (cell adhesion molecule, cell membrane)

  16. Spatial patterns (cell sorting) 3000steps Initial 500steps 8000steps

  17. Simulation example Medium Normal cellτ1 Initiated cell τ2 Progressed cell τ3 Cancer cell τ4 Large mutation rates are used for the time limitation.

  18. Mutation rate vs. Cancer cell production NO cancer Cancer emergence Mutation rate of normal cell

  19. Conclusion • Our ongoing study about initial to cellular level biological radiation effects using computer modeling and simulations is showed. • LET dependency of the DNA damage complexity is studied. • Relationship between structural change of damaged DNA and its repair is studied. • Cellular level dynamics of the carcinogenesis is modeled and parameter (mutation rates) dependency is examined.

  20. Thanks! JAEA Dr. Ritsuko Watanabe : Simulation of DNA damage induction Dr. Miroslav Pinak : Simulation of DNA repair Dr. Julaj Kotulic Bunta : Simulation of Ku70/80 binding Dr. Mariko Higuchi : Simulation of multiple lesioned DNA NIID Dr. Hideaki Maekawa : DNA damage induction experiment Dr. Hirofumi Fujimoto : DNA repair simulation NIRS Dr. Manabu Koike : DNA repair experiment

  21. JAEA JAEA J-PARC

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