Lipophilicity of Coarse-Grained Cholesterol Models

The lipophilicity of cholesterol was investigated by using coarse-grained molecular dynamics and umbrella sampling. The previous coarse-grained cholesterol models in the literature are more hydrophobic than our model. The Gibbs free energy of transferring cholesterol from the octanol phase to water phase (Δ G o/w ) was 11.88 ± 0.08 kcal mol –1, and the octanol–water partitioning coefficient (logP) was estimated to be 8.72 ± 0.06. The latter is in agreement with the logP values found by bioinformatics, which are standard methods to predict the lipophilicity, giving excellent octanol/water partitioning coefficients compared with experimental ones for different molecules. We also performed the first experimentally direct measurement of this important property for cholesterol. The experimental octanol/water partitioning coefficient of cholesterol was measured to be 8.86 ± 0.79, which is in excellent agreement with our calculated logP value from our parametrized coarse-grained cholesterol model. This shows the significance of systematic optimization of the lipophilicity for developing coarse-grain models of important biomolecules with complicated molecular structures and hydrophobic character like cholesterol.