Purpose: To study the biological meaning of site in microdosimetry and DNA direct damage at different degrees of DNA compactness under alpha particle irradiation.
Methods: To associate the concept of site in microdosimetry with a biological endpoint, we performed TOPAS-nBio simulations of direct damage caused by alpha particles to two DNA arrangements in a water sphere of 500 nm radius: (i) straight linear plasmids of DNA, i.e., double helix arranged in parallel, with axial separations of 2.8 nm, 4.2 nm, and 5.6 nm; and (ii) supercoiled plasmids of DNA (pBR322) available in TOPAS-nBio. DNA geometries were uniformly irradiated by an isotropic source of alpha particles with initial energies between 1 and 15 MeV/u. Scored double strand breaks (DSBs) were defined as damage (i.e., energy imparted above 17.5 eV) in two base pairs separated by less than 10 base pairs. Yield of DSBs per Gy per giga base pair (Gbp) were obtained and reported as a function of the corresponding dose-mean lineal energy (y_D) and dose-mean specific energy (z_D(r)) for sites of variable size.
Results: Yields of DSBs in the linear plasmids, regardless of the separation between them, showed the same linear relation with y_D. Yields of DSBs for supercoiled plasmids were greater than for linear plasmids but also exhibited an approximately linear relation. Yields as a function of z_D(r) from both linear and supercoiled configurations were aligned for radii equal to 385 nm and 293 nm, respectively.
Conclusion: Compacted DNA have neighbor base pairs closer than uncoiled DNA, which makes a track more likely to damage two of them. This associates with smaller volumes in which the pattern of energy deposited is relevant, i.e., smaller sites. Therefore, prediction of direct DNA induction from microdosimetry can be separated into two components: y_D (radiation quality-dependent) and site radius (DNA geometry-dependent).
Funding Support, Disclosures, and Conflict of Interest: This work was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grant no. R01 CA187003.