Interestingly we note that the F104A mutant is well predicted and presents an unoccluded pathway toward solvent. Similarly, M102A residence time is well predicted and its binding site could be easily solvent-exposed upon simple rotamer changes. On the contrary, the L99A mutant presents a much more buried binding site that would require a more substantial rearrangement. This correlates well with the residence time overprediction and it is a typical signature of metadynamics missing some relevant details in its CVs (see Supporting Information).