Computational investigation of hydrogen abstraction and aqueous interaction of thyroxine: a combined DFT and molecular dynamics study

Thyroxine is a key thyroid hormone involved in metabolic regulation, growth, and neurological development. This study investigates its molecular stability and reactivity using density functional theory (DFT) and molecular dynamics (MD) simulations. Hydrogen bond dissociation energies (H-BDEs) were calculated at the B3LYP/def2-TZVP level to identify sites susceptible to hydrogen abstraction and oxidative degradation. Results indicate that hydroxyl groups and carbon–hydrogen bonds adjacent to heteroatoms are the most favorable sites for radical attack. Solvent effects were evaluated, showing that water slightly alters H-BDE values and can either promote or inhibit hydrogen abstraction depending on the site. MD simulations with explicit water at the GFN-FF level reveal detailed solvation behavior. Radial distribution function analysis highlights strong hydrogen bonding between water and oxygen-containing groups, with additional interactions involving iodine atoms. Overall, the findings provide molecular-level insight into thyroxine stability, reactivity, and degradation pathways in aqueous environments. These findings offer valuable insight into its stability under environmental and biological conditions and may contribute to future studies on thyroid hormone behavior and transformation pathways.