Computer modeling of radiation effects
20th International CODATA Conference 25 October 2006, Beijing
Noriyuki B. Ouchi and Kimiaki Saito
Japan Atomic Energy Agency
Radiation Effects Analysis Research Group, Nuclear Science and Engineering Directorate,
Table of Contents
3. 4. 5.
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
-- organ/tissue damage (or death)
High Dose effect
Late time (stochastic) effect
-- radiation induced cancer
At low dose region, quantitative risk estimation are not so easily obtained.
Low dose radiation risk risk = probability of cancer incidence
Assessment by extrapolation
Risk estimation at low dose radiation needs further study based on the Biological mechanisms.
Scale of the++
Cellular level simulation
Initial process of the μm DNA damage (10-6) nm (10-9)
DNA Repair DNA damage
Basis of risk estimation DNA lesion repair
hour day year
ionization Å (10-10) 10-15s 10-9s
2. Initial process of radiation induced DNA Damage
Radiation to the cell nucleus causes damage to DNA
Biologicall y important damage Single Strand Break (SSB) Double Strand Break (DSB)
What kind of radiation with what type of track generate how much damages ?
To clarify the relations between track structure and DNA strand breaks.
Track structure 1. 2. 3. 4.
Track structure calculation Radical production DNA modeling Calculating DNA and radical reactions Target DNA modeling
Track structure: spatial distribution of energy deposition of ionizing radiation
DNA damage induction simulation (proton + solenoid DNA)
Result [SSB/DSB ratio]
Indicator of complexity of DNA damage
25 20 15 10 5
LET [Linear Energy Transfer] energy deposition by the charged particle per unit path length
100 101 102 LET (keV/um)
DSB yield increasing with LET up to 100 keV/m
3. Molecular dynamical study of the DNA lesion repair
Molecular Dynamics simulation
V (ri ) 2ri (t ) Fi mi ri t 2
Position of each atoms (i)
mi mass Fi Force acting on atom i
V (ri ) Potential energy of the system
(ri (0), ri (0)) Initial condition (configuration)
To clarify a dependency between damaged DNA structural change and capability of the DNA repair.
Shape change of damaged DNA
Damaged DNA: 8oxo-G + AP site Native DNA (no damage)
•Damaged DNA shows bending movement at leisioned site •Dynamic analysis of DNA structure is ongoing.
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.
τ2 Ppm τ3
kd : Prob. of cell death
PI, Ppm, Pc : prob. of cell state change (genetic)
t : normal, initiation, promotion, cancer
If a(s) > ac then cell division occur
Details of the model
Intracellular state change affects the physical parameters (cell adhesion molecule, cell membrane)
τ τ τ τ
(J1, a1, l1 ) (J2, a2, l2 ) (J3, a3, l3 ) (J4, a4, l4 )
Spatial patterns (cell sorting)
Medium Normal cell
Initiated cell τ2 Progressed cell τ3
Cancer cell τ4
Large mutation rates are used for the time limitation.
Mutation rate vs. Cancer cell production
NO cancer Cancer emergence
Mutation rate of normal cell
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.
Dr. Ritsuko Watanabe : Dr. Miroslav Pinak : Dr. Julaj Kotulic Bunta : Dr. Mariko Higuchi : Simulation of DNA damage induction Simulation of DNA repair Simulation of Ku70/80 binding Simulation of multiple lesioned DNA
Dr. Hideaki Maekawa : Dr. Hirofumi Fujimoto :
DNA damage induction experiment DNA repair simulation
Dr. Manabu Koike :
DNA repair experiment