Interaction between tr yptophan, 5-hydr oxy-tr yptophan and serotonin with model membranes studied

I. WOOD; M PICKHOLZ

Córdoba

Congreso; Congreso Argentino de Bioinformática y Biología Computacional; 2011

Universidad de Córdoba

Interaction between tryptophan, 5-hydroxy-tryptophan and serotonin with model membranes studied by molecular dynamics simulations Irene Wood, Mónica Pickholz Department of Pharmaceutical Technology, University of Buenos Aires, Buenos Aires, CP 1113, Argentina Background Serotonin (5-HT) is a neurotransmitter and hormone implicated in several physiological processes by activating multiple receptors. Abnormalities on the serotoninergic system have been implicated in many psychiatric disorders such as anxiety, depression, psychosis, migraine, and others. Otherwise, 5-HT is synthesized by a two-step reaction from the essential amino acid tryptophan (Trp) through 5-hydroxytryptophan (5-HTP). Both Trp and 5-HT penetrate to the central nervous system (CNS) through the blood-brain barrier (BBB), facilitated by transporters [[1]]. However there is not data supporting that5-HTP crosses BBB by a specific carrier. In this work, we use Molecular Dynamic simulations (MDs) - which provide a unique tool for analyzing the properties of these systems from an atomic perspective with a level of detail missing in experimental techniques- to study the interactions of serotonin and its precursors. Materials and methods MDs were performed at constant pressure (1atm) and temperature (310K), in order to 1-palmitoil-2-oleoil-sn-glicero-3-phosphatidyl-choline (POPC) bilayers to be found in the fluid lamellar phase. Four different guest molecules were studied: Trp, 5-HTP and both charged and neutral 5-HT. Serotonin is essentially found protonated at physiological pH. Each system consists in 2 identical guest molecules, 4200 molecules of water and 150 POPC molecules. Each simulation was run up 50 ns. Results From the analysis of the electron density profiles, we found that the four guest molecules are essentially located at the water-lipid head interface. Specific interactions were studied through the analysis of radial distribution functions. For example, for the 5-HTP case, the analysis of the radial distribution of pairs of atoms N amino group (5-HTP) and O phosphate group (POPC) shows a well defined peak ~ 1.7 Å characteristic of hydrogen bond. Conclusions During the simulation time length, we did not observe any crossing events between the monolayers for any of the guest molecules. All of them are found in the lipid-water interface. This behavior and the structural similarity, suggests that 5-HTP, like Trp and 5-HT, would require a carrier to cross BBB. References [[1]] Ohtsuki S: New Aspects of the Blood–Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System. Pharm. Bull.2004, 27: 1489-1496.