Computer modeling of
radiation effects
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
1.
Introduction
2.
Simulation of DNA strand breaks
by ionizing radiation
3.
Molecular dynamical study of the
DNA lesion repair
4.
Modeling and simulation of the
cellular level tumorigenesis
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
High Dose effect
Dose-Response
Dose
C
a
n
ce
r
in
ci
d
e
n
ce
Low dose
Assessment by extrapolation
Scale of the++
Radical reactions
Carcinogenesis
Tumorigenesis
10-15s 10-9s 10-6s sec. min. hour day year
Gene-mutation DNA damage ionization cm mm (10-3)
μm (10-6)
nm (10-9)
Å (10-1 0)
Basis of risk estimation
DNA Repair
Initial process of the DNA damage
2. Initial process of radiation induced
DNA Damage
To clarify the relations between track structure
and DNA strand breaks.
Radiation to the cell nucleus causes damage
to DNA
Single Strand Break (SSB)
Double Strand Break (DSB)
What kind of radiation with what type of track generate
how much damages ?
Question: Biologica
Simulation method
Track structure Radical production
Target DNA modeling
Radical diffusion
1. Track structure calculation 2. Radical production
3. DNA modeling
4. Calculating DNA and radical reactions
Simulation example
DNA damage induction
simulation
(proton + solenoid DNA)
DNA damage induction
simulation
0 5 10 15 20 25 30 35
10-1 100 101 102 103
linear nucleosome Ra ti o (S SB /D SB ) LET (keV/um)
α
proton
photon
60Co 10keV 1MeV 135keV 344keV 1MeVResult
[SSB/DSB ratio]
nucleosome model
linear
model
LET [Linear Energy Transfer] energy deposition by the charged particle per unit path length
DSB yield increasing with LET up to 100 keV/
m
3. Molecular dynamical study of
the DNA lesion repair
Molecular Dynamics simulation
2 2
(
)
)
(
t
t
m
V
F
i i i i i
r
r
r
H H O))
0
(
,
)
0
(
(
r
ir
i Initial condition (configuration)i
r
Position of each atoms (i)i
m
massi
F
Force acting on atom i)
(
iV
r
Potential energy of the systemTo clarify a dependency between damaged DNA
Shape change of damaged
DNA
1.3 ns
8-oxoG
AP site
2.0 ns
Damaged DNA: 8oxo-G + AP site Native DNA (no damage)
Clustered damage
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.
τ
4τ
3Intracellular dynamics
k
d1k
d2k
d3k
d4P
CP
IP
pmCell division
k
d:
Prob. of cell death
cell state
normal, initiation, promotion,
cancer
P
I, P
pm, P
c: prob. of cell state change (genetic)
τ
2Cell transformation
Details of the model
Intracellular state change affects the physical
parameters
(cell adhesion molecule, cell membrane)
τ
１τ
2τ
3τ
4(J
1,
a
1,
l
1)
(J
2,
a
2,
l
2)
(J
3,
a
3,
l
3)
Spatial patterns (cell
sorting)
Simulation example
Medium
Initiated cell
τ
2 Normal cell １τ
1Cancer cell
τ
4Progressed cell
τ
3Mutation rate vs. Cancer cell
production
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
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
JAEA
