Reactive molecular dynamics study of methotrexate degradation by non-thermal plasma

The increasing presence of chemotherapeutic drug residues in aquatic environments presents a significant challenge due to their poor biodegradability and potential toxicity. Methotrexate (MTX), a widely used anticancer agent, is largely excreted unmetabolized and enters wastewater streams, where conventional treatment methods often fail to degrade it effectively. Advanced oxidation processes (AOPs) have been explored for MTX removal, with non-thermal plasma (NTP)-based treatments emerging as a promising environmentally sustainable alternative. Recent experimental studies have shown that a non-thermal pencil plasma jet can achieve substantial degradation and mineralization of MTX, thereby reducing its toxicity in treated water. However, the molecular-level degradation mechanisms and intermediate reaction pathways remain insufficiently understood. In this study, we employ computer simulations to investigate the atomic-scale oxidative degradation processes of MTX induced by NTP-generated reactive oxygen species (ROS). Specifically, we use reactive molecular dynamics (MD) to study the interaction of oxygen atoms (key ROS species) with MTX. By simulating critical reaction pathways and degradation kinetics, we aim to complement experimental findings and provide mechanistic insights into MTX degradation under NTP treatment. Our results reveal key degradation mechanisms including hydroxylation, ring opening and fragmentation with CO 2 release, which elucidate how oxygen radicals progressively destabilize and decompose the MTX molecule, leading to reduced toxicity. Our simulation results are in qualitatively align with the experimental observations.The integration of computational and experimental approaches enhances our understanding of plasma-induced pharmaceutical degradation, supports the development of optimized wastewater treatment strategies.