Section S4 further examines the natural soft-core properties of the DE-FF and the convergence of the reported free energy calculations with the λ -schedule. In brief, a naive linear scaling of the potential with λ causes convergence issues, but by additionally scaling down the α and β parameters of eq 2 we obtain very similar convergence properties as the LJ soft-core potential (Section S4). For both the LJ soft core and DE-FF, we are even able to pare the annihilation legs of the calculation down to six λ windows, from the default of 16, with < 0.1 kcal/mol change in free energy (Table ). That is, the natural soft core of DE-FF shows very similar convergence properties to the optimised LJ soft core, without the additional coding complexity of changing functional form for free energy calculations.