The benefits of a rigorous thermodynamic approach like iMetaD lie in its ability to compute the absolute residence time without the need for an extensive calibration procedure. Additionally, the use of a rigorous thermodynamic approach can further provide hints on the causes of inaccurate predictions and offer guidance to improve them. An underestimation may be caused by an improper preparation or incorrect template-docked structure while overestimation are more due to orthogonal degrees of freedom not captured by the ligand-driven CVs (e.g. protein motion). This last point is also the main limitation of the current approach. The reader would have noticed that for the T4 lysozyme case, the overprediction was noticeable. In this system, a sidechain rotamer change, not explicitly modeled by the path CVs, was required for path egress but still, the method was somehow predictive. This allows us to speculate on qualitative criteria for the workflow success: the binding pocket must be solvent-exposed enough to let the ligand desorb without major protein backbone and sidechain rearrangements.