Microscopic Interactions of Melatonin, Serotonin and Tryptophan with Zwitterionic Phospholipid Membranes.

The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10-20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10-7 cm2/s for the cholesterol-free and cholesterol-rich setups.

Naturally occurring melatonin: Sources and possible ways of its biosynthesis.

According to recent reports, the global market for melatonin is worth 700 million USD in 2018 and would reach 2,790 million USD by 2025, growing at a CAGR of 18.9% during 2019 to 2025. Having regard to the prevalence of sleep and circadian rhythm disorders and a clear tendency to increase the demand for melatonin, and the current lack of alternative green and cost-efficient technologies of its synthesis, the supply of this remedy will not be enough to guarantee melatonin supply and affordability on a global scale. The emergence of naturally occurring melatonin and its isomers in fermented foods has opened an exciting new research area; there are still, however, some obscure points in the efficient microbiological biosynthesis of melatonin. This review summarizes the research progress and recent evidence related to melatonin and its isomers in various foodstuffs. Additionally, one possible way to synthesize melatonin is also discussed. The evidence pointed out that the presence of melatonin and its isomers is not exclusive for grapes and grape-derived products, because it can be also found in sweet and sour cherries. However, different species of both Saccharomyces and non-Saccharomyces yeasts could be used to obtain melatonin and melatonin isomers in the process of alcoholic fermentation biotechnologically. The availability of L-tryptophan has been a key factor in determining the concentration of indolic compounds produced, and the utilization of probiotic lactic acid bacteria could help in the formation of melatonin isomers during malolactic fermentation. These approaches are environmentally friendly alternatives with a safer profile than conventional ones and could represent the future for sustainable industrial-scale melatonin production.