Chapter 4 - The fundamental interaction of cholesterol with lipid membranes: The umbrella model

Abstract

Cholesterol is the most interesting and the most studied membrane molecule. The knowledge of its fundamental interaction with other molecules can help us to understand the biological functions of cholesterol. This article reviews a conceptual model, the Umbrella model, which has been developed to describe the key interaction between cholesterol and other membrane lipids. The cholesterol molecule has a small polar hydroxyl headgroup and a large nonpolar body (i.e., the steroidal ring structure). The imbalance in size of polar headgroup vs. nonpolar body determines that cholesterol in a lipid bilayer partially relies on the coverage from the headgroups of neighboring lipids to avoid the unfavorable free energy of cholesterol contact with water. This coverage requirement leads to some interesting behaviors; thus, cholesterol prefers lipids with a large headgroup and saturated acyl chains, produces the “condensing effect” and reduces membrane permeability, is capable of inducing formation of membrane domains, has a strong tendency to minimize the size of its own clusters in a bilayer, and competes with other small-headgroup molecules, such as ceramide and diacylglycerol, for large headgroup lipids. A number of important experiments, thermodynamics calculations, and computer simulations that have been used to develop and validate the Umbrella model will be discussed. The Umbrella model can be used as an effective tool to understand and predict the behavior of cholesterol in biomembranes.