Early DNA Damage Study at the Molecular Scale in a Proton-Irradiated Scenario: A Full Assessment of Tetranucleosome...

DNA is highly susceptible to damage from high-energy particles, making molecular-level computation of DNA damage essential for understanding the underlying molecular mechanisms. In this study, we conducted an in-depth investigation of DNA strand breaks. We computed hydrogen-abstraction preferences from deoxyribose by hydroxyl radicals using the DNA segment of the nucleosome tetramer structure (Protein Data Bank entry 1ZBB) enclosed in a 2.5-fold water box. Additionally, we explored the equilibrium distribution of the neutral sugar radical deoxynucleosides. Our findings indicate that the reaction preference is primarily governed by solvent accessibility. Using this model, we calculated the number of DNA strand breaks induced by hydroxyl radicals generated by water radiolysis, a form of indirect damage. Combined with the modified number of strand breaks from direct damage, we achieved agreement with experimental yields of SSBs and DSBs. This study combines Geant4-DNA Monte Carlo calculations with Gaussian Density Functional Theory calculations, offering valuable insights into the biological effects and therapeutic implications of early DNA damage, particularly in the context of structurally elucidated DNA.