Abstract
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.
Highlights
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
Three sets of two-dimensional (2D) well-tempered metadynamics simulations based on the specific collective variables (CV) defined above were performed to calculate free-energy surfaces of MEL at cholesterol contents of 0%, 30% and 50% at neutral zwitterionic DMPC membranes
Such orientations are in excellent agreement with the average values of Ψ obtained from ordinary Molecular dynamics (MD) simulations[60] and they correspond to the two folded and extended geometries of melatonin previously observed
Summary
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. 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. Despite the significant progress of free energy calculations achieved in recent years[64,65,66], to the best of our knowledge the free energy landscape of melatonin and most of small solutes on membrane surfaces is still mostly unknown This is partially due to the difficulty of applying appropriate sampling techniques to address the problem, and because of the complexity of the membrane environments, making the determination of the proper collective variables a difficult challenge[67]. We will discuss the role of cholesterol in the cellular absorption of small molecules
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