Mechanistic Modeling of Radiation-Induced Plasmid DNA Damage Measured By Atomic Force Microscopy
Abstract
Purpose
Supercoiled plasmid DNA is widely used to study radiation-induced DNA damage. High-resolution atomic force microscopy (AFM) measurements of radiation-induced DNA fragment-length distributions have directly provided quantitative insights into radiation effects. In this study, we employ a GPU-accelerated microscopic Monte Carlo simulation (MMCS) framework to model these experiments.
Methods
A geometrical model of a double-stranded pUC-19 plasmid with 2684 base pairs was constructed. 4000 plasmids were randomly distributed within a 2 μm³ cubic volume. Radiation interactions were simulated covering physical, pre-chemical, and chemical stages, and reactions with DNA molecules. DNA double strand breaks were recorded and fragment length distributions were calculated up to 6000 Gy. A realistic 6 MeV electron LINAC spectrum, recorded after 1 cm water, was used as the irradiation source. The effects of chemical interaction probability (P) and chemical stage duration (T) were systematically evaluated.
Results
GPU-accelerated framework enabled plasmid fragmentation simulations to compute 170 Gy per hour computation time. Simulated fragment-length distributions with T = 20 ns and P = 0.4 showed good agreement with AFM experimental measurements across the investigated dose range. The fitted parameter k of the Parke model was 8.59 MGy⁻¹, consistent with AFM experimental value of 8.5 ± 0.5 MGy⁻¹. At 6000 Gy with T = 20 ns and P = 0.4, the fragment-to-plasmid ratio for LINAC irradiation was 3.6, significantly lower than 18.6 for 4.5 keV electron irradiation. Increasing P from 0.1 to 0.8 resulted in an approximately linear increase in fragment production, while extending T from 5 ns to 20 ns increased the fragment-to-plasmid ratio from 1.9 to 3.6 at 6000 Gy.
Conclusion
GPU-accelerated MMCS accurately reproduced experimental observations, validating the proposed framework. This capability enables simulations for future mechanistic investigations of radiation-induced DNA damage under diverse irradiation conditions.