Metadynamics is not able to recover the correct ranking but again it can effectively quantify the absolute values of residence time (Figure ). It is interesting to note that we observe a large number of unfruitful iMetaD simulations for 4F6W. This ligand has a molecular weight and flexibility that is significantly larger than the other ligands in the series and in general larger than an average drug-like compound (see Supporting Information). We suspect that a path description here may fail since the RMSD metrics are highly degenerate with respect to any change in the dihedral space hence the ligand could easily end up at a point in the phase space for which the path CVs have not been designed. To put it differently, the path definition in the RMSD space provides an insufficient description of the process of interest. This results in the inability of iMetaD to get out of these free energy traps hence the applicability of the method in the current incarnation for this complex is questionable. Here again, similarly to the p38 system, we think this metric is a useful proxy of how much one can trust results that have been generated with this method. Adenosine A 2A Receptor (A 2A )