Kinetic assessment of DNA double-strand breaks via coarse-grained molecular dynamics simulations

Deoxyribonucleic acid (DNA) is the biological macromolecule holding the hereditary information required by cells to replicate and carry out their activity.
However, DNA is constantly threatened by a variety of endogenous and exogenous agents, among which ionizing radiation (IR) is of particular significance. In fact, within the variety of DNA lesions, the impact of IR on cells is associated with a plethora of modifications, at both a molecular and a functional level, which may result in deleterious effects for the cell survival. Among these, DNA double-strand breaks (DSBs), i.e. the disruption of the covalent bonds on the sugar-phosphate backbone of both complementary DNA strands, have been acknowledged as the fingerprint of IR. These lesions are associated with severe cytotoxic effects, especially when they are highly-condensed within localized DNA volumes. The action of ionizing radiation (IR) is inherently multiscale, ranging from the initial energy deposition at the nanometre scale to complex biological responses occurring over extended timescales. Due to the difficulty of in vitro experiment to access the early stages of the DNA damage cascade of processes, numerical simulations provide a powerful tool in describing both the radiation interactions and the mechanical and thermodynamic properties of DNA under different environmental conditions.
This PhD research focuses on the characterization of the DNA rupturing process by DNA DSB through coarse-grained molecular dynamics (MD) simulations. The results indicate that DNA rupture can be described as a cooperative, thermally-activated process that follows the Poisson statistics. After analyzing the impact of the DNA supercoiling and sequence-dependent effects on the structural dynamics of DNA minicircles, this work demonstrates how various structural and mechanical factors—as well as the degree of DNA supercoiling—can contribute in modulating the DNA rupturing process. 
Overall, these findings emphasize the potential of coarse-grained MD simulations in providing valuable insights into the characterization of the radiation-induced DNA damage.