The chemical stage of the Monte Carlo track-structure (MCTS) code Geant4-DNA was extended for its use in DNA strand break (SB) simulations and compared against published experimental data. Geant4-DNA simulations were performed using pUC19 plasmids (2686 base pairs) in a buffered solution of DMSO irradiated by60Co or137Csγ-rays. A comprehensive evaluation of SSB yields was performed considering DMSO, DNA concentration, dose and plasmid supercoiling. The latter was measured using the super helix density value used in a Brownian dynamics plasmid generation algorithm. The Geant4-DNA implementation of the independent reaction times method (IRT), developed to simulate the reaction kinetics of radiochemical species, allowed to score the fraction of supercoiled, relaxed and linearized plasmid fractions as a function of the absorbed dose. The percentage of the number of SB after •OH + DNA and H• + DNA reactions, referred as SSB efficiency, obtained using MCTS were 13.77% and 0.74% respectively. This is in reasonable agreement with published values of 12% and 0.8%. The SSB yields as a function of DMSO concentration, DNA concentration and super helix density recreated the expected published experimental behaviors within 5%, one standard deviation. The dose response of SSB and DSB yields agreed with published measurements within 5%, one standard deviation. We demonstrated that the developed extension of IRT in Geant4-DNA, facilitated the reproduction of experimental conditions. Furthermore, its calculations were strongly in agreement with experimental data. These two facts will facilitate the use of this extension in future radiobiological applications, aiding the study of DNA damage mechanisms with a high level of detail.

Department of Radiation Dosimetry Nuclear Physics Institute of the Czech Academy of Sciences Prague Czech Republic

Department of Radiation Oncology Massachusets General Hospital and Hardvard Medical School Boston MA United States of America

Department of Radiation Oncology University of California San Francisco San Francisco CA United States of America

Faculty of Mathematics and Physics Sciences Benemérita Universidad Autónoma de Puebla Puebla Mexico

Laboratoire de Dosimétrie des Rayonnements Ionisants Institut de Radioprotection et Sûreté Nucléaire Fontenay aux Roses BP 17 F 92262 France

Univ Bordeaux CNRS IN2P3 CENBG UMR 5797 F 33170 Gradignan France

Zobrazit více v PubMed

Aydogan B, Bolch WE, Swarts SG, Turner JE, & Marshall DT (2008). Monte Carlo simulations of site-specific radical attack to DNA bases. Radiation Research, 169(2), 223–231. 10.1667/RR0293.1 PubMed DOI

Berger MJ, Seltzer SM (1973). ETRAN, Monte Carlo code system for electron and photon transport through extended media. Retrieved from https://rsicc.ornl.gov/PackageDetail.aspx?p=ETRAN&id=C00107&cpu=I0360&v=00&t=Monte Carlo Code System for Electron and Photon Through Extended Media.

Bernal MA, Bordage MC, Brown JMC, Davídková M, Delage E, El Bitar Z, … Incerti S (2015). Track structure modeling in liquid water: A review of the Geant4-DNA very low energy extension of the Geant4 Monte Carlo simulation toolkit. Physica Medica, 31(8), 861–874. 10.1016/j.ejmp.2015.10.087 PubMed DOI

Booz J, & Feinendegen LE (1988). A microdosimetric understanding of low-dose radiation effects. International Journal of Radiation Biology, 53(1), 13–21. 10.1080/09553008814550381 PubMed DOI

Buxton GV, Greenstock CL, Helman WP, & Ross AB (1988). Critical Review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (⋅OH/⋅O− in Aqueous Solution. Journal of Physical and Chemical Reference Data, 17(2), 513–886. 10.1063/1.555805 DOI

Casali N, & Preston A (2003). E.coli Plasmid Vectors. Methods in molecular biology (Vol. 253). Totowa, New Jersey: Humana Press. 10.1007/978-1-60761-820-1_12 DOI

Charlton DE, Nikjoo H, & Humm JL (1989). Calculation of Initial Yields of Single-Strand and Double-Strand Breaks in Cell-Nuclei From Electrons, Protons and Alpha-Particles. International Journal of Radiation Biology, 56(1), 1–19. 10.1080/09553008914551141 PubMed DOI

Chatterjee A, & Magee JL (1985). Theoretical Investigation of the Production of Strand Breaks in DNA by Water Radicals. Radiation Protection Dosimetry, 13(1–4), 137–140.

Clifford P, Green NJB, Oldfield MJ, Pilling MJ, & Pimblott SM (1986). Stochastic models of multi-species kinetics in radiation-induced spurs. Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 82(9), 2673–2689. 10.1039/F19868202673 DOI

Cobut V, Frongillo Y, Patau JP, Goulet T, Fraser MJ, & Jay-Gerin JP (1998). Monte Carlo simulation of fast electron and proton tracks in liquid water - I. Physical and physicochemical aspects. Radiation Physics and Chemistry, 51(3), 229–243. 10.1016/S0969-806X(97)00096-0 DOI

Cowan R, Collis CM, & Grigg GW (1987). Breakage of double-stranded DNA due to single-stranded nicking. Journal of Theoretical Biology, 127(2), 229–245. 10.1016/S0022-5193(87)80133-9 PubMed DOI

de la Fuente Rosales L, Incerti S, Francis Z, & Bernal MA (2018). Accounting for radiation-induced indirect damage on DNA with the Geant 4-DNA code. Physica Medica, 51(June), 108–116. 10.1016/j.ejmp.2018.06.006 PubMed DOI

Dizdaroglu M, & Jaruga P (2012). Mechanisms of free radical-induced damage to DNA. Free Radical Research, 46(4), 382–419. 10.3109/10715762.2011.653969 PubMed DOI

Edel S, Terrissol M, Peudon A, Kümmerle E, & Pomplun E (2006). Computer simulation of strand break yields in plasmid pBR322: DNA damage following 125I decay. Radiation Protection Dosimetry, 122(1–4), 136–140. 10.1093/rpd/ncl453 PubMed DOI

Ermak DL, & McCammon JA (1978). Brownian dynamics with hydrodynamic interactions. The Journal of Chemical Physics, 69(4), 1352–1360. 10.1063/1.436761 DOI

Figueroa-González G, & Pérez-Plasencia C (2017). Strategies for the evaluation of DNA damage and repair mechanisms in cancer. Oncology Letters, 13(6), 3982–3988. 10.3892/ol.2017.6002 PubMed DOI PMC

Friedland W, Bernhardt P, Jacob P, Paretzke HG, Dingfelder M, Cherubini R, … Ottolenghi A (2002). Simulation of DNA damage after proton and low let irradiation. Radiation Protection Dosimetry, 99(1–4), 99–102. 10.1093/oxfordjournals.rpd.a006848 PubMed DOI

Friedland Werner, Dingfelder M, Kundrát P, & Jacob P (2011). Track structures, DNA targets and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 711(1–2), 28–40. 10.1016/j.mrfmmm.2011.01.003 PubMed DOI

Gao Y, Zheng Y, Sanche L. Low-Energy Electron Damage to Condensed-Phase DNA and Its Constituents. International Journal of Molecular Sciences. 2021; 22(15):7879. 10.3390/ijms22157879 PubMed DOI PMC

Georgakilas AG, O’Neill P, & Stewart RD (2013). Induction and repair of clustered DNA lesions: What do we know so far? Radiation Research, 180(1), 100–109. 10.1667/RR3041.1 PubMed DOI

Green NJB, Pilling MJ, Pimblott SM, & Clifford P (1990). Stochastic modeling of fast kinetics in a radiation track. Journal of Physical Chemistry, 94(1), 251–258. 10.1021/j100364a041 DOI

Hall EJ, & Giaccia AJ (2012). Radiobiology for the radiologist: Seventh edition. Radiobiology for the Radiologist: Seventh Edition (7th ed.).

Hart EJ, & Boag JW (1962). Absorption Spectrum of the Hydrated Electron in Water and in Aqueous Solutions. Journal of the American Chemical Society, 84(21), 4090–4095. 10.1021/ja00880a025 DOI

Hempel K, & Mildenberger E (1987). Determination of g-values for single and double Strand break induction in plasmid DNA using agarose gel electrophoresis and a curve-fitting procedure. International Journal of Radiation Biology, 52(1), 125–138. 10.1080/09553008714551551 PubMed DOI

Huang J, Schlick T, & Vologodskii A (2001). Dynamics of site juxtaposition in supercoiled DNA. Proceedings of the National Academy of Sciences of the United States of America, 98(3), 968–973. 10.1073/pnas.98.3.968 PubMed DOI PMC

Incerti S, Baldacchino G, Bernal M, Capra R, Champion C, Francis Z, … Zacharatou C (2010). THE Geant4-DNA project. International Journal of Modeling, Simulation, and Scientific Computing, 1(2), 157–178. 10.1142/S1793962310000122 DOI

Incerti S, Ivanchenko A, Karamitros M, Mantero A, Moretto P, Tran HN, … Zacharatou C (2010). Comparison of GEANT4 very low energy cross section models with experimental data in water. Medical Physics, 37(9), 4692–4708. 10.1118/1.3476457 PubMed DOI

Incerti S, Kyriakou I, Bernal MA, Bordage MC, Francis Z, Guatelli S, … Brown JMC (2018). Geant4-DNA example applications for track structure simulations in liquid water: A report from the Geant4-DNA Project. Medical Physics, 0(0), 1–18. 10.1002/mp.13048 PubMed DOI

Karamitros M, Luan S, Bernal MA, Allison J, Baldacchino G, Davidkova M, … Incerti S (2014). Diffusion-controlled reactions modeling in Geant4-DNA. Journal of Computational Physics, 274, 841–882. 10.1016/j.jcp.2014.06.011 DOI

Karamitros Mathieu, Mantero A, Incerti S, Friedland W, Baldacchino G, Barberet P, … Zacharatou C (2011). Modeling Radiation Chemistry in the Geant4 Toolkit. Progress in Nuclear Science and Technology, 2(0), 503–508. 10.15669/pnst.2.503 DOI

Kassis AI, Harapanhalli RS, & Adelstein SJ (1999a). Comparison of strand breaks in plasmid DNA after positional changes of Auger electron-emitting iodine-125. Radiation Research, 151(2), 167–176. 10.2307/3579767 PubMed DOI

Kassis AI, Harapanhalli RS, & Adelstein SJ (1999b). Strand breaks in plasmid DNA after positional changes of auger electron- emitting iodine-125: Direct compared to indirect effects. Radiation Research, 152(5), 530–538. 10.2307/3580150 PubMed DOI

Klenin K, & Langowski J (2000). Computation of writhe in modeling of supercoiled DNA. Biopolymers, 54(5), 307–317. 10.1002/1097-0282(20001015)54:5<307::AID-BIP20>3.0.CO;2-Y PubMed DOI

Klimczak U, Ludwig DC, Mark F, Rettberg P, & Schulte-Frohlinde D (1993). Irradiation of plasmid and phage DNA in water-alcohol mixtures: Strand breaks and lethal damage as a function of scavenger concentration. International Journal of Radiation Biology, 64(5), 497–510. 10.1080/09553009314551711 PubMed DOI

Lampe N, Karamitros M, Breton V, Brown JMC, Kyriakou I, Sakata D, … Incerti S (2018). Mechanistic DNA damage simulations in Geant4-DNA part 1: A parameter study in a simplified geometry. Physica Medica, 48(February), 135–145. 10.1016/j.ejmp.2018.02.011 PubMed DOI

Lampe N, Karamitros M, Breton V, Brown JMC, Sakata D, Sarramia D, & Incerti S (2018). Mechanistic DNA damage simulations in Geant4-DNA Part 2: Electron and proton damage in a bacterial cell. Physica Medica, 48(June), 146–155. 10.1016/j.ejmp.2017.12.008 PubMed DOI

Leenhouts HP, & Chadwick KH (1985). Radiation Energy Deposition In Water Calculation of DNA Damage and Its Association with RBE. Radiation Protection Dosimetry, 13(1–4), 267–270.

Meesungnoen J, Benrahmoune M, Filali-Mouhim A, Mankhetkorn S, & Jay-Gerin J-P (2001). Monte Carlo Calculation of the Primary Radical and Molecular Yields of Liquid Water Radiolysis in the Linear Energy Transfer Range 0.3–6.5 keV/?m: Application to 137 Cs Gamma Rays1. Radiation Research, 155, 269–278. 10.1667/0033-7587(2001)155[0269:mccotp]2.0.co;2 PubMed DOI

Meylan S, Vimont U, Incerti S, Clairand I, & Villagrasa C (2016). Geant4-DNA simulations using complex DNA geometries generated by the DnaFabric tool. Computer Physics Communications, 204, 159–169. 10.1016/j.cpc.2016.02.019 DOI

Meylan Sylvain, Incerti S, Karamitros M, Tang N, Bueno M, Clairand I, & Villagrasa C (2017). Simulation of early DNA damage after the irradiation of a fibroblast cell nucleus using Geant4-DNA. Scientific Reports, 7(1), 1–15. 10.1038/s41598-017-11851-4 PubMed DOI PMC

Milligan JR, Aguilera JA, & Ward JF (1993). Variation of single-strand break yield with scavenger concentration for plasmid DNA irradiated in aqueous solution. Radiation Research, 133(2), 151–157. 10.2307/3578350 PubMed DOI

Milligan JR, Arnold AD, & Ward JF (1992). The effect of superhelical density on the yield of single-strand breaks in γ-irradiated plasmid DNA. Radiation Research, 132(1), 69–73. 10.2307/3578335 PubMed DOI

Milligan JR, Wu CCL, Ng JY-Y, Aguilera JA, & Ward JF (1996). Characterization of the Reaction Rate Coefficient of DNA with the Hydroxyl Radical. Radiation Research, 146(5), 510. 10.2307/3579551 PubMed DOI

Nelder JA, & Mead R (1965). A Simplex Method for Function Minimization. The Computer Journal, 7(4), 308–313. 10.1093/comjnl/7.4.308 DOI

Nikjoo H, Uehara S, Willson WE, Hoshi M, & Goodhead DT (1998). Track structure in radiation biology: theory and applications. International Journal of Radiation Biology, 73(4), 355–364. Retrieved from http://informahealthcare.com/doi/abs/10.1080/095530098142176 PubMed DOI

Patrick Higgins N, & Vologodskii AV (2015). Topological Behavior of Plasmid DNA. Plasmids, 3(2), 105–131. 10.1128/9781555818982.ch7 PubMed DOI PMC

Perl J, Shin J, Schümann J, Faddegon B, & Paganetti H (2012). TOPAS: An innovative proton Monte Carlo platform for research and clinical applications. Medical Physics, 39(11), 6818–6837. 10.1118/1.4758060 PubMed DOI PMC

Perry CC, Ramos-Méndez J, & Milligan JR (2020). DNA condensation with a boron-containing cationic peptide for modeling boron neutron capture therapy. Radiation Physics and Chemistry, 166(September 2019), 108521. 10.1016/j.radphyschem.2019.108521 PubMed DOI PMC

Peukert C, Incerti S, Kempson I, Douglass M, Karamitros M, Baldacchino G and Bezak E (2019) Validation and investigation of reactive species yields of Geant4-DNA chemistry models Medical Physics (46):983–98. 10.1002/mp.13332 PubMed DOI

Pimblott SM, & Green NJB (1992). Stochastic modeling of partially diffusion-controlled reactions in spur kinetics. Journal of Physical Chemistry, 96(23), 9338–9348. 10.1021/j100202a052 DOI

Pimblott SM, & LaVerne JA (1997). Stochastic simulation of the electron radiolysis of water and aqueous solutions. Journal of Physical Chemistry A, 101(33), 5828–5838. 10.1021/jp970637d DOI

Plante I (2011). A Monte-Carlo step-by-step simulation code of the non-homogeneous chemistry of the radiolysis of water and aqueous solutions. Part I: Theoretical framework and implementation. Radiation and Environmental Biophysics, 50(3), 389–403. 10.1007/s00411-011-0367-8 PubMed DOI

Ramos-Méndez J, Domínguez-Kondo N, Schuemann J, McNamara A, Moreno-Barbosa E, & Faddegon B (2020). LET-dependent intertrack yields in proton irradiation at ultra-high dose rates relevant for FLASH therapy. Radiation Research, 194(4), 351–362. 10.1667/RADE-20-00084.1 PubMed DOI PMC

Ramos-Méndez J, Perl J, Schuemann J, McNamara A, Paganetti H, & Faddegon B (2018). Monte Carlo simulation of chemistry following radiolysis with TOPAS-nBio. Physics in Medicine and Biology, 63(10), 0–12. 10.1088/1361-6560/aac04c PubMed DOI PMC

Ramos-Méndez José, Shin WG, Karamitros M, Domínguez-Kondo J, Tran NH, Incerti S, … Faddegon B (2020). Independent reaction times method in Geant4-DNA: Implementation and performance. Medical Physics. 10.1002/mp.14490 PubMed DOI PMC

Sakata D, Belov O, Bordage MC, Emfietzoglou D, Guatelli S, Inaniwa T, … Incerti S (2020). Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA. Scientific Reports, 10(1), 1–13. 10.1038/s41598-020-75982-x PubMed DOI PMC

Sakata D, Lampe N, Karamitros M, Kyriakou I, Belov O, Bernal MA, … Incerti S (2019). Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA. Physica Medica, 62(January), 152–157. 10.1016/j.ejmp.2019.04.010 PubMed DOI

Shin W-G, Ramos-Mendez J, Hoang Ngoc T, Perrot Y, Incerti S, Okada S, & Villagrasa C (2021). Geant4-DNA simulation of the pre-chemical stage of water radiolysis and its impact on initial radiochemical yields. Physica Medica, 88(77), 86–90. PubMed PMC

Shin WG, Ramos-Mendez J, Faddegon B, Tran HN, Villagrasa C, Perrot Y, … Incerti S (2019). Evaluation of the influence of physical and chemical parameters on water radiolysis simulations under MeV electron irradiation using Geant4-DNA. Journal of Applied Physics, 126(11). 10.1063/1.5107511 DOI

Takata H, Hanafusa T, Mori T, Shimura M, Iida Y, Ishikawa K, … Maeshima K (2013). Chromatin Compaction Protects Genomic DNA from Radiation Damage. PLoS ONE, 8(10), 1–11. 10.1371/journal.pone.0075622 PubMed DOI PMC

Toburen L (2014). Development of Monte Carlo Track Structure Codes. Nasa, 2–6. Retrieved from https://three.jsc.nasa.gov/articles/Monte-Carlo-Track-Structure-Toburen.pdf

Tomita H, Kai M, Kusama T, & Ito A (1998). Monte Carlo simulation of DNA strand-break induction in supercoiled plasmid pBR322 DNA from indirect effects. Radiation and Environmental Biophysics, 36(4), 235–241. 10.1007/s004110050077 PubMed DOI

Tomita Hiroyuki, Kai Y, & Kusama AT (1995). Strand Break Formation in Plasmid DNA Irradiated in Aqueous Solution: Effect of Medium Temperature and Hydroxyl Radical Scavenger Concentration. Radiat. Res, 36, 46–55. PubMed

Turner JE, Magee JL, & Wright HA (1983). Physical and chemical development of electron tracks in liquid water. Radiation Research, 96(3), 437–449. 10.2307/3576111 DOI

Vologodskii AV, & Nicholas CR (1994). Conformational And Thermodynamic Properties of Supercoiled DNA. Annu. Rev. Biophys. Struct, (23). PubMed

Vyšín L, Pachnerová Brabcová K, Štěpán V, Moretto-Capelle P, Bugler B, Legube G, … Davídková M (2015). Proton-induced direct and indirect damage of plasmid DNA. Radiation and Environmental Biophysics, 54(3), 343–352. 10.1007/s00411-015-0605-6 PubMed DOI

Watanabe R, Rahmanian S, & Nikjoo H (2015). Spectrum of Radiation-Induced Clustered Non-DSB Damage - A Monte Carlo Track Structure Modeling and Calculations. Radiation Research, 183(5), 525–540. 10.1667/RR13902.1 PubMed DOI

Wright HA, Magee JL, Hamm RN, Chatterjee A, Turner JE, & Klots CE (1985). Calculations of Physical And Chemical Reactions Produced in Irradiated Water Containing DNA. Radiation Protection Dosimetry, 13(1–4), 133–136.

Zaider M, Brenner DJ, & Wilson WE (1983). The applications of track calculations to radiobiology I. Monte Carlo simulation of proton tracks. Radiation Research, 95(2), 231–247. 10.2307/3576252 DOI