These new results reduced the overestimation for these systems, reducing the overall RMSE to 1.08 as shown in Figure . We hypothesize that applying high RAMD forces to systems with low energy barriers (or equivalently fast unbinding rates) disturbs the free energy profile and the sampled distribution of paths too much. In this case, the algorithm may fail to select an appropriate path CV because of an unrealistic pathway produced or an erroneous distribution of paths, which is likely to be more sensitive than fitting the mean simulation time. While the mean and variance of the RAMD simulation time are informative for setting these sampling parameters, we need to develop new recommendations for when to tune them in this setting and leave this task for future studies.