The characterization of interactions between melatonin, one main ingredient of medicines
regulating sleeping rhythms, and basic components of cellular plasma membranes (phos-
pholipids, cholesterol, metal ions and water) is very important to elucidate the main mecha-
nisms for the introduction of melatonin into cells and also to identify its local structure and
microscopic dynamics. Molecular dynamics simulations of melatonin inside mixtures of
dimyristoylphosphatidylcholine and cholesterol in NaCl solution at physiological concentra-
tion have been performed at 303.15 K to systematically explore melatonin-cholesterol, mel-
atonin-lipid and melatonin-water interactions. Properties such as the area per lipid and
thickness of the membrane as well as selected radial distribution functions, binding free
energies, angular distributions, atomic spectral densities and translational diffusion of mela-
tonin are reported. The presence of cholesterol significantly affects the behavior of melato-
nin, which is mainly buried into the interfaces of membranes. Introducing cholesterol into the
system helps melatonin change from folded to extended configurations more easily. Our
results suggest that there exists a competition between the binding of melatonin to phospho-
lipids and to cholesterol by means of hydrogen-bonds. Spectral densities of melatonin
reported in this work, in overall good agreement with experimental data, revealed the partici-
pation of each atom of melatonin to its complete spectrum. Melatonin self-diffusion coeffi-
cients are of the order of 10 -7 cm 2 /s and they significantly increase when cholesterol is
addeed to the membrane.
