However, the systems used by Paliwal et al. are small toy models and hence are not relevant for larger protein-ligand systems as used in this work. One of the ways in which uncertainty is quantified in their work was to run an ensemble of 100 simulations and calculate the mean and standard deviation of the binding free energies from each simulation. Using large ensembles allowed Paliwal et al. to quantify the type of distribution for calculated hydration free energies. From the calculated binding free energy distributions, it is concluded that the assumptions of Gaussian distributed errors in free energies are usually valid for most methods studied. This is contrary to the observations made in our work where, when using the same free energy estimators for an investigation of more complex protein-ligand systems, it is found that Gaussian distributions cannot be assumed, as also reported in some of our previous studies .