Calculation of the water-octanol partition coefficient of cholesterol for SPC, TIP3P, and TIP4P water.

We present a numerical study of the relative solubility of cholesterol in octanol and water. Our calculations allow us to compare the accuracy of the computed values of the excess chemical potential of cholesterol for several widely used water models (SPC, TIP3P, and TIP4P). We compute the excess solvation free energies by means of a cavity-based method [L. Li et al., J. Chem. Phys. 146(21), 214110 (2017)] which allows for the calculation of the excess chemical potential of a large molecule in a dense solvent phase. For the calculation of the relative solubility ("partition coefficient," log₁₀Po/w ) of cholesterol between octanol and water, we use the OPLS/AA force field in combination with the SPC, TIP3P, and TIP4P water models. For all water models studied, our results reproduce the experimental observation that cholesterol is less soluble in water than in octanol. While the experimental value for the partition coefficient is log₁₀Po/w = 3.7, SPC, TIP3P, and TIP4P give us a value of log₁₀Po/w = 4.5, 4.6, and 2.9, respectively. Therefore, although the results for the studied water models in combination with the OPLS/AA force field are acceptable, further work to improve the accuracy of current force fields is needed.