Investigation of the Interactions of Carbamazepine with Lipid Membranes: Insights from Molecular Dynamics Simulations and NMR Experiments

Carbamazepine (CBZ) is a widely used anticonvulsant whose pharmacological effects include state- and use-dependent inhibition of voltage-gated sodium channels in neuronal membranes. Because CBZ interacts with these targets within a lipid environment, its membrane partitioning, preferred depth, orientation, and influence on bilayer organization are critical to understanding its physicochemical context of action. This study combines solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations to investigate CBZ interactions with a POPC bilayer, a well-established model of phospholipid membranes. Through 1H MAS NOESY, 2H, and 31P NMR experiments, the location of CBZ and its effects on lipid chain order and phosphocholine headgroup dynamics were determined. Both experimental and computational approaches demonstrated that CBZ preferentially associates with the lipid–water interface. Molecular dynamics density profiles revealed that CBZ primarily localizes near the glycerol/phosphocholine region, with the amide group favoring the polar interfacial environment and the tricyclic moiety extending further into the membrane. This localization was corroborated by the highest 1H–1H NOESY cross-relaxation rates for the glycerol/phosphocholine segments. At the simulated CBZ concentration, the overall POPC bilayer structure remained largely unchanged, with no significant alterations in acyl-chain order or area per lipid. However, 31P NMR indicated a slight increase in phosphocholine headgroup mobility in the presence of CBZ. These findings suggest that CBZ accumulates strongly at the POPC membrane interface while causing only minimal disruption to overall bilayer organization, thereby providing a lipid-level framework for future studies in more complex neuronal and ion-channel-containing membranes.