The Molecular Interplay Between Lipids, Cholesterol and Membrane Hydration Layer

Understanding membrane structure, including its hydration, is vital for unraveling the chemistry of life. The nanoscopic layer of water directly hydrating biological membranes plays a critical role in maintaining cell structure, regulating biochemical processes, and mediating intermolecular interactions at the membrane interface. Cholesterol-rich lipid rafts, on the other hand, facilitate membrane fusion-a process essential for neurotransmitter release, fertilization, and viral entry-with localized, transient membrane dehydration serving as a key step in this process. This chapter summarizes the recent efforts to elucidate the intricate, three-way molecular interplay between membrane lipids, cholesterol, and the interfacial hydration layer. We begin by discussing the membrane-composition-specific effect of cholesterol on the arrangement of water molecules that form the membrane hydration layer. We highlight how interactions between cholesterol and different lipids lead to orientational anisotropy of the water molecules, resulting in a heterogeneous membrane dipole potential, which plays a role in domain-selective cellular processes, such as protein binding. Next, we consider the redistribution of cholesterol content within phase-separated lipid membranes induced by changes in the membrane's hydration state. This observation provides a new perspective on the regulatory role of cell membrane heterogeneity during membrane fusion. Finally, we discuss how to disentangle the ability of water and cholesterol to modulate lipid membranes' fluidity. The concluding remarks highlight pressing questions and key challenges that remain to be tackled in the field, paving the way for future research.