Hydration Free Energies of Linear Alkanes: Systematic Deviations in Common Water Models and Their Correction

Abstract

Common force fields overestimate the hydration free energies of hydrophobic solutes, leading to an exaggerated hydrophobic effect. We compute the hydration free energies of linear alkanes from methane to eicosane (C${20}$H${42}$) using free energy perturbation with various three-site (SPC/E, OPC3) and four-site (TIP4P/2005, OPC) water models in combination with the TraPPE-UA alkane force field. All water models overestimate hydration free energies, although the four-site models perform better than the three-site ones. Using alkane cavity free energies, we reparameterize the alkane-water Lennard-Jones well depth to bring simulation results in agreement with experimental and group-contribution estimates at 300 K. The reparameterized models significantly improve agreement with experiments across temperatures (290--350 K). We also show that the General Amber Force Field (GAFF) with TIP4P/2005 water provides closer agreement with experimental hydration free energies than the original TraPPE-UA/TIP4P/2005 combination. Finally, we show that applying a shifted Lennard-Jones potential introduces systematic deviations in the hydration free energies.