Comprehensive Insights into the Cholesterol-Mediated Modulation of Membrane Function through Molecular Dynamics Simulations

Abstract: Cholesterol plays an essential role in biological membranes and is crucial for maintaining their stability and functionality. It is necessary for a variety of membranes, including planar bilayers, liposomes, curved bilayers, nanodiscs, and proteoliposomes. Cholesterol regulates membrane properties by influencing the density of lipids, phase separation into liquid-ordered (Lo) and liquid-disordered (Ld) areas, and stability of protein--membrane interactions. For planar bilayers, cholesterol thickens the membrane, decreases permeability, and brings lipids into well-ordered domains, adding rigidity and fluidity. It modulates membrane curvature in curved bilayers and vesicles, and stabilises low-curvature regions, which are important for structural integrity. In liposomes, cholesterol facilitates drug encapsulation and release by controlling bilayer flexibility and stability. In nanodiscs, cholesterol enhances structural integrity and protein compatibility, which enables the investigation of protein--lipid interactions under physiological conditions. In proteoliposomes, cholesterol regulates the conformational stability of embedded proteins that have implications for protein--lipid interaction. Developments in molecular dynamics (MD) techniques, from coarse-grained to all-atom simulations, have shown how cholesterol modulates lipid tail ordering, membrane curvature, and flip-flop behaviour in response to concentration. Such simulations provide insights into the mechanisms underlying membrane-associated diseases, aiding in the design of efficient drug delivery systems. In this review, we combine results from MD simulations to provide a synoptic explanation of cholesterols complex function in regulating membrane behaviour.