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

) 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 the 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 the 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.