Throughout this work uncertainties were computed via bootstrap, unless explicitly specified otherwise, and represent standard deviations when taking into account all available calculations. Bootstrapping was performed for the individual repeats of free energy predictions for each ligand based on the work values, the final free energy prediction for each ligand across multiple repeats, as well as for AUE and Pearson correlation functions across multiple ligands. Actual values around which these uncertainties are reported are still the means (or results of the AUE and correlation functions) of the underlying data, not the means of the bootstrapped distributions.