Résumé : The analgesic dipeptide kyotorphin (L-Tyr-L-Arg) and an acylated kyotorphin derivative were studied by a combination of theoretical (molecular dynamics simulation and quantum mechanics methods) and experimental (fluorescence and infrared spectroscopies) approaches both in solution and in model systems of membranes. At biological pH the peptides have a neutral net charge. Nevertheless, their phenolic rings interact with phospholipid molecules (partition coefficient varies from 6 x 10(2) to 2 x 10(4), depending on the lipid and pH used) despite being exposed to the aqueous bulk medium. The lowest energy transition dipole moment is displaced from the normal to the lipid bilayer by 20 degrees on average. The observed extensive interaction, pK(a), precise location, and well-defined orientation in membranes combined with the ability to discriminate rigid raftlike membrane domains suggest that kyotorphin meets the structural constraints needed for receptor-ligand interaction. The acylated kyotorphin derivative mimics kyotorphin properties and represents a promising way for entrapment in a drug carrier and transport across the blood-brain barrier.