Computer modelling of radiation effects

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					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
1.
2.

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
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1. Introduction
 Radiation Effects
 Deterministic effect
-- 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

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Dose-Response

Cancer incidence

Low dose
Assessment by extrapolation

Dose
Risk estimation at low dose radiation needs further study based on the Biological mechanisms.
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Scale of the++
cm
Cellular level simulation
Tumorigenesis

mm (10-3)
Carcinogenesis

Initial process of the μm DNA damage (10-6) nm (10-9)

Gene-mutation

Radical reactions

DNA Repair DNA damage

Basis of risk estimation DNA lesion repair
hour day year
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ionization Å (10-10) 10-15s 10-9s

10-6s

sec.

min.

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)

Question:

What kind of radiation with what type of track generate how much damages ?

To clarify the relations between track structure and DNA strand breaks.
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Simulation method

Track structure 1. 2. 3. 4.

Radical production

Radical diffusion

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

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Result [SSB/DSB ratio]
Indicator of complexity of DNA damage

35 30
Ratio (SSB/DSB)

25 20 15 10 5

60Co

linear nucleosome

10keV

photon

proton α
1MeV

linear model

nucleosome model

135keV

1MeV
344keV

LET [Linear Energy Transfer] energy deposition by the charged particle per unit path length

0 10-1

100 101 102 LET (keV/um)

103

DSB yield increasing with LET up to 100 keV/m
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3. Molecular dynamical study of the DNA lesion repair
Molecular Dynamics simulation
O H

V (ri )  2ri (t ) Fi    mi ri t 2

ri
H

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.
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Simulation example

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Shape change of damaged DNA
Damaged DNA: 8oxo-G + AP site Native DNA (no damage)

1.3 ns

2.0 ns

AP site

8-oxoG

Clustered damage

•Damaged DNA shows bending movement at leisioned site •Dynamic analysis of DNA structure is ongoing.
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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.

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Intracellular dynamics
Cell transformation

τ1
kd1

PI

τ2 Ppm τ3
kd2 kd3

PC

τ4
kd4

kd : Prob. of cell death
PI, Ppm, Pc : prob. of cell state change (genetic)
cell state

t : normal, initiation, promotion, cancer

Cell division
If a(s) > ac then cell division occur
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Details of the model
Intracellular state change affects the physical parameters (cell adhesion molecule, cell membrane)

τ τ τ τ

1

(J1, a1, l1 ) (J2, a2, l2 ) (J3, a3, l3 ) (J4, a4, l4 )
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2

3

4

Spatial patterns (cell sorting)

Initial

500steps

3000steps

8000steps

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Simulation example
Medium Normal cell

τ1

Initiated cell τ2 Progressed cell τ3
Cancer cell τ4

Large mutation rates are used for the time limitation.
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Mutation rate vs. Cancer cell production
NO cancer Cancer emergence

Mutation rate of normal cell
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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.

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Thanks!
JAEA
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

NIID

Dr. Hideaki Maekawa : Dr. Hirofumi Fujimoto :

DNA damage induction experiment DNA repair simulation

NIRS

Dr. Manabu Koike :

DNA repair experiment

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JAEA

J-PARC

JAEA

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