Force Switching and Potential Shifting Lead to Significant Cutoff Dependence in Alchemical Free Energies

The accurate treatment of long-range energy terms such
as van der
Waals interactions is crucial for reliable free energy calculations
in molecular simulations. Methods like force switching, potential
switching, potential shifting, and Ewald summation of van der Waals
are commonly employed to smooth the truncation or otherwise manage
these interactions at and beyond a cutoff distance, but their effects
on free energy calculations are not always clear. In this study, we
systematically explore the effects of these modifiers on the accuracy
of free energy calculations using model systems: Lennard-Jones spheres,
all-atom anthracene in water with GROMACS, and alkane chains in water
with LAMMPS. Our results reveal that free energies of solvation using
potential switching and particle-mesh Ewald summation of long-range
Lennard-Jones are essentially independent of cutoff in solution, while
force switching and potential shifting introduce cutoff-dependent
behavior that is significant enough to affect the utility of the calculations.