SUMMARY

New tools have recently been developed to simulate nano-scale radiation track structure and chemical species resulting from the radiolysis of water, record the resulting DNA damage, and model the pathways of DNA repair. These tools allow for in silico investigation of cell radiosensitivity and how it is influenced by several factors, such as the arrangement of chromosomes in the cell nucleus. This work presents a pipeline employing in vitro Hi-C chromosome conformation capture data to create specific cell nucleus models which are then used in TOPAS-nBio radiation simulations. The DNA double-strand breaks (DSBs) are recorded, and then their repair is mechanistically simulated in MEDRAS-MC. This pipeline is used to predict not only the initial radiation-induced DNA damage, but also the repair outcomes resulting from this damage in order to investigate the role chromosome conformation plays in the biological outcome of radiation exposure. The results of the simulated DNA repair are compared with in vitro data to validate the pipeline. This work also aims to establish a method using libraries of DNA damage files, each consisting of DSB data resulting from a single track of high-LET radiation, to efficiently predict DNA repair outcomes in a variety of scenarios. These libraries are created by running many TOPAS-nBio simulations of a single proton or alpha track for a range of energies and recording the DNA damage. A suitable number of these data files can be superimposed according to the desired dose, type, and energy of radiation. Then, MEDRAS-MC can be used to simulate the repair outcomes of this superimposed radiation damage. These libraries will allow for the study of multiple applications, such as neutron therapy or targeted alpha therapy, without the need for time-consuming simulations of high-LET radiation track structure.