Protonation-dependent interactions of amitriptyline with DPPC lipid bilayers: a molecular dynamics study

The protonation state of amphiphilic drugs strongly influences their interactions with biological membranes, affecting their partitioning and permeability. Here, united-atom molecular dynamic simulations were performed to investigate the interactions of neutral and protonated amitriptyline (AMI) with a dipalmitoylphosphatidylcholine (DPPC) bilayer. Membrane structural and dynamic properties were evaluated using density profiles, area per lipid, bilayer thickness, deuterium order parameters, lateral diffusion coefficients and radial distribution functions. The results revealed distinct membrane-interaction mechanisms depending on AMI protonation. Protonated AMI preferentially localised at the lipid-water interface, forming strong electrostatic interactions with DPPC phosphate groups, whereas neutral AMI readily partitioned into the hydrophobic core and underwent transbilayer migration. Neutral AMI induced greater acyl-chain ordering, while protonated AMI caused comparatively smaller perturbations to the membrane core. Although both forms enhanced lipid lateral diffusion, phosphate-phosphate RDF analysis indicated that the overall lateral membrane organisation remained largely unchanged. These findings highlight the importance of drug protonation in governing membrane localisation, intermolecular interactions and membrane dynamics.