Indirect DNA damage by hydroxyl radicals: a molecular dynamics assessment

Radiation-induced DNA damage is a complex, multiscale process involving ionization, radical formation, and subsequent chemical reactions that can lead to biological effects. Molecular dynamics (MD) simulations, in principle, offer a powerful approach for studying these phenomena by evolving a fully atomistic representation of the system over time. Reactive force fields, such as ReaxFF, enable the simulation of bond breaking, formation, and charge transfer, allowing the prediction of reaction pathways, kinetic constants, and diffusion properties without predefined reactive species. However, accurately modeling radiation-induced damage remains challenging due to biomolecules' representation, the complexity of reactive species, and the need for precise parameterization. In this work, we employed a multi-step approach using reactive MD simulations with various ReaxFF parametrizations and alternative charge equilibration methods. We first assessed the accuracy of different ReaxFF models in describing the reactivity and diffusion of hydroxyl radicals, requiring modifications to the original force field. We then evaluated the stability of a periodic DNA fragment under these force fields, using periodic boundary conditions to ensure consistent behavior. The focus was on identifying reliable parametrizations and charge models that accurately represent radical dynamics and DNA stability. The interaction between hydroxyl radicals and DNA will be studied by examining different spatial distributions of radicals under various radiation conditions to accurately assess the probability and nature of damage Preliminary results show that certain ReaxFF parametrizations, combined with appropriate charge models, can accurately describe hydroxyl radical behavior, overcoming limitations observed in previous approaches. Initial stability assessments indicate that the force field is suitable for modeling DNA in a reactive environment, although ongoing work aims to validate this further. This work introduces a new tool for radiation damage assessment in different radiation field conditions and advances the use of MD for studying radiation-induced DNA damage by refining force field approaches.