Binding free energies of small-molecules in phospholipid membranes: Aminoacids, serotonin and melatonin

Abstract

Free energy barriers associated to the binding of small-molecules at phospholipid zwitterionic membranes have been computed at 323 K for a variety of species: tryptophan, histidine, tyrosine, serotonin and melatonin bound to a model membrane formed by di-palmitoyl-phosphatidyl-choline lipids inside aqueous sodium chloride so- lution. We have computed the radial distribution functions of all species for a variety of membrane and water- related sites and extracted potentials of mean force through the reversible work theorem. In all cases but his- tidine, the molecular probes are able to either be fully solvated by water or be embedded into the interface of the membrane. Our results indicate that binding of all species to water corresponds to free energy barriers of heights between 0.2 and 1.75 kcal/mol. Free energy barriers of association of small-molecules to lipid chains range between 0.6 and 3.1 kcal/mol and show different characteristics: all species but histidine are most likely bound to oxygens belonging to the phosphate and to the glycerol groups. Histidine shows a clear preference to be fully solvated by water whereas the aqueous solvation of serotonin is the less likely case of them all. No free per- meation through the membrane of any small-molecule has been observed during the time span of the simulation experiments.