The Beta Trypsin-benzamidine complex is a classical benchmark for free energy approaches since it is a small system with a relatively low number of degrees of freedom. Hence it has been studied extensively by standard molecular dynamics, Metadynamics 27,72-74 , Dissipation-corrected Targeted-MD, Ligand-Gaussian Accelerated MD, and Umbrella Sampling 77 among others. Additionally, Beta Trypsin has been kinetically and thermodynamically characterized by competitive inhibition with proflavin. Our results show a residence time for benzamidine of (4.28 ± 1.34) x 10 -1 sec which compares favorably with other techniques and, despite its small size, the system is challenging due to the complex roles played by solvent and protein flexibility. For proflavin we predict a residence time of (1.99 ± 0.47) x 10 -5 sec which compares well with 1.05 x 10 -4 sec from the experiment. Additionally, the proflavin complex had to be modeled in place, using alpha-thrombin as a template (see Supporting Information) adding a further layer of uncertainty. We simulated unbinding for 29 ligands across 5 receptors. Among these 29, the majority of ligands achieved a 100% unbinding success rate and only 2 achieved success rates below 90%. Despite the high success rate, few ligands had exponentially distributed unbinding times according to the KS test (see Supporting Information for all statistics), possibly due to the method sampling multiple egress paths per ligand or due to the inherent complexity of the unbinding profile in the learned CV space. In lieu of the KS test, we can still use the above 90% unbinding rate threshold to assess which systems have unreliable predictions. When calculating the overall metrics, we omitted bottom-of-assay ligands because they can no longer be used to assess ranking capabilities when they are in the middle of the full experimental range. The overall RMSE was 1.22 which led to a good ranking with Spearman ρ of 0.90 and R 2 of 0.80 as shown in Figure . Strikingly, the worst discrepancies between experimental and predicted residence times were in the benchmark systems with fast-unbinding fragments. We hypothesize that the default sampling parameters are inappropriate for this regime of residence times and investigate these systems in the following section. We designed the workflow to assist in the prediction of residence time during drug design cycles. Compared to T4 Lysozyme or Beta Trypsin binders, these ligands tend to have a larger molecular weight and make more hydrophobic and directional interactions. Hence the free energy wells are in general deeper and present a steeper contour. We designed the various parameters in the workflow with this application in mind. In particular, the RAMD spring constant has been set to compensate for this steeper potential. Up to here, we presented the reader with an objective view of how the workflow performs on the entire set when using default parameters. In this section, we present a series of experiments to understand which sampling parameters were inappropriate and how to tune them in cases with suboptimal results.