Cholesterol Chemical Potential in Mixed Phosphatidylcholine/Cholesterol Bilayer: Model Predictions and Computer Simulations

Abstract

Cholesterol plays a vital role in maintaining the structure of cellular membranes by inducing order and increasing packing. There are multiple competing models that aim to describe the structure of cholesterol-containing phospholipid bilayers, and these models make specific predictions for the concentration dependence of the cholesterol chemical potential. In this work, we systematically study four phosphatidylcholine (PC) lipids with different degrees of unsaturation to investigate which of these models best describes the bilayer behavior. We use coarse-grained molecular dynamics simulations together with replica exchange umbrella sampling to calculate the transfer free energy of one cholesterol molecule from the bilayer to bulk water, from which we infer the chemical potential. Our results demonstrate the sensitivity of the chemical potential to the degree of PC tail unsaturation and show that cholesterol has the greatest affinity to saturated PC lipids. Contrary to recent experiments and the conceptual models, our results indicate that the chemical potential increases linearly with increasing cholesterol concentration for all lipid types, suggesting the absence of critical cholesterol concentrations at which the bilayer organization changes dramatically. The increase of the chemical potential with cholesterol content also suggests that cholesterol prefers bilayers with lower cholesterol concentration.