摘要：Free energy calculations are essential to unveil mechanisms at the atomic scale such as binding of small solutes and their translocation across cell membranes, eventually producing cellular absorption. Melatonin regulates biological rhythms and is directly related to carcinogenesis and neurodegenerative disorders. Free energy landscapes obtained from well-tempered metadynamics simulations precisely describe the characteristics of melatonin binding to specific sites in the membrane and reveal the role of cholesterol in free energy barrier crossing. A specific molecular torsional angle and the distance between melatonin and the center of the membrane along the normal to the membrane Z-axis have been considered as suitable reaction coordinates. Free energy barriers between two particular orientations of the molecular structure (folded and extended) have been found to be of about 18 kJ/mol for z-distances of about 1–2 nm. The ability of cholesterol to expel melatonin out of the internal regions of the membrane towards the interface and the external solvent is explained from a free energy perspective. The calculations reported here offer detailed free energy landscapes of melatonin embedded in model cell membranes and reveal microscopic information on its transition between free energy minima, including the location of relevant transition states, and provide clues on the role of cholesterol in the cellular absorption of small molecules.
