of the edges agreed with experiment within the threshold for the least performing target (SHP2). On the other hand, 78% of edges in the best performing target (TNKS2) were correct considering the threshold. This difference between least and best performing target can be reduced with the Consensus approach, which seems to correct for large outliers. Various reasons can lead to a disproportionate number of outliers for a few targets. One reason can be inaccuracies in the setup of the starting structures. This could be wrong starting poses of the ligand, inadequate protein preparation or unlikely protonation or tautomeric states, both in ligand and in protein. If all force fields show low performance for a specific target it suggests a common preparation error. The protein and ligands might be more flexible in certain targets, and the free energy estimate only converges if two or more conformational states are sampled sufficiently. Thus more sampling or even enhanced sampling would be needed to adequately model such a target. Some targets have ligand sets with more difficult perturbations. For example, charge changes, charge moves or the creation/annihilation of large moieties like cyclohexyl groups are difficult perturbations which either would require longer sampling times, or are even better treated with absolute binding free energy approaches.