Effects of cholesterol on the binding of the precursor neurotransmitter tryptophan to zwitterionic membranes

The characterization of the microscopical forces between the essential α-amino-acid tryptophan, precursor of the neurotransmitter serotonin and of the hormone melatonin, and the basic components of cell membranes and their environments (phospholipids, cholesterol, ionic species, and water) is of central importance to elucidate their local structure and dynamics as well as the mechanisms responsible for the access of tryptophan to the interior of the cell. We have performed nanosecond molecular dynamics simulations of tryptophan embedded in model zwitterionic bilayer membranes made by di-palmitoyl-phosphatidyl-choline and cholesterol inside aqueous sodium-chloride solution in order to systematically examine tryptophan-lipid, tryptophan-cholesterol, and tryptophan-water interactions under liquid-crystalline phase conditions. Microscopic properties such as the area per lipid, lipid thickness, radial distribution functions, hydrogen-bonding lengths, atomic spectral densities, and self-diffusion coefficients have been evaluated. Our results show that the presence of tryptophan significantly affects the structure and dynamics of the membrane. Tryptophan spends long periods of time at the water-membrane interface, and it plays a central role by bridging a few lipids and cholesterol chains by means of hydrogen-bonds. The computed spectral densities, in excellent agreement with experimental infrared and Raman data, revealed the participation of each atomic site of tryptophan to the complete spectrum of the molecule. Tryptophan self-diffusion coefficients have been found to be in between 10^-7 and 10^-6 cm²/s and strongly depending of the concentration of cholesterol in the system.