Hydration Free Energies of Linear Alkanes: Evaluating and Correcting Classical Force Field Predictions with Different Water Models

Abstract: Common force fields tend to 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 and the TraPPE-UA force field for alkanes. All water models overestimate the hydration free energies, though the four-site models perform better than the three-site ones. By utilizing cavity free energies, we reparameterize the alkane--water well depth to bring simulation results in agreement with experimental and group-contribution estimates. We find that the General Amber Force Field (GAFF) combined with TIP4P/2005 water provides closer estimates of the hydration free energy. The HH alkane model (a reparameterized TraPPE-UA force field) with TIP4P/2005 reproduces experimental hydration free energies. We also show that applying a shifted Lennard--Jones potential leads to systematic deviations in the hydration free energy estimates.