n this article, we investigate the mechanisms of DNA ionization upon irradiation by 0.5 meV alpha particles. We focus on the sugar-phosphate group and its hydration shell. In radiation chemistry, the term quasi-direct effect refers the physical and chemical responses taking place after irradiation of solvent molecules pertaining to the solvation shells of solutes. The molecular mechanisms accounting for the quasi-direct effect are actually largely elusive, especially for those prevailing in the early timescales (< 10^–12 s). We report Real-Time Time-Dependent Auxiliary Density Functional Theory simulations carried out within the framework of hybrid QM/MM scheme (Quantum Mechanics/Molecular Mechanics) with polarizable and non-polarizable embedding. Ten water molecules from the solvation shell of DNA backbone are independently irradiated. We find that during the first femtoseconds after irradiation, the holes formed on the irradiated water remain at their sites of formation. Electrostatic induction within the environment does not significantly impact charge migrations. We address the hypothesis that charge migration driven by electron correlation is responsible for an ultrafast H₂O⁺ to DNA charge transfers, which would account for a quasi-direct effect. We find that pure charge migration at fixed nuclear positions is not responsible for the quasi-direct effect when considering sugar-phosphate solvation shells.

The primary processes that occur following direct irradiation of bio-macromolecules by ionizing radiation determine the multiscale responses that lead to biomolecular lesions. The so-called physical stage loosely describes processes of energy deposition and molecular ionization/excitation but remains largely elusive. We propose a new approach based on first principles density functional theory to simulate energy deposition in large and heterogeneous biomolecules by high-energy-transfer particles. Unlike traditional Monte Carlo approaches, our methodology does not rely on pre-parametrized sets of cross-sections, but captures excitation, ionization and low energy electron emission at the heart of complex biostructures. It furthermore gives access to valuable insights on ultrafast charge and hole dynamics on the femtosecond time scale. With this new tool, we reveal the mechanisms of ionization by swift ions in microscopic DNA models and solvated DNA comprising almost 750 atoms treated at the DFT level of description. We reveal a so-called ebb-and-flow ionization mechanism in which polarization of the irradiated moieties appears as a key feature. We also investigate where secondary electrons produced by irradiation localize on chemical moieties composing DNA. We compare irradiation of solvated DNA by light (H⁺, and He²⁺) vs. heavier (C⁶⁺) ions, highlighting the much higher probability of double ionization with the latter. Our methodology constitutes a stepping stone towards a greater understanding of the chemical stage and more generally towards the multiscale modelling of radiation damage in biology using first principles.