orders of magnitude. While the QMrebind+SEEKR2 method has shown k off prediction accuracy for most of the Hsp90-inhibitor complexes, certain outliers underscore inherent challenges and limitations of this method. For the Hsp90-ligand 37 complex, the estimated k off of (3.82 ± 0.05) × 10 2 s -1 is significantly higher than the experimentally determined k off of (2.0 ± 0.2) × 10 -3 s -1 , and is essentially predicted by QMrebind+SEEKR2 to be a fast unbinder. We choose to define an outlier as any complex whose predicted k off is greater than two orders of magnitude distant from the experimental k off . For the outlier complex of ligand 37, reparameterizing partial charges of the ligand via QMrebind did not produce close-to-experiment k off . The inaccurate k off estimate for the Hsp90-ligand 37 complex can likely be attributed to other deficiencies within the model. In our assessment, it is possible that starting structures generated via SMD simulations do not always correctly sample the unbinding pathway. Unfortunately, attempts to pull the ligand more slowly out of the binding pocket via SMD simulations to generate starting structures to resolve the problem have not improved the kinetic estimates (data not shown). It is also possible that a better choice of CV, apart from the ligand-binding site COM-COM distance, would produce better kinetics, as it may lead to more extensive sampling within the Voronoi cells. Several attempts have been made to identify the exact causes of these discrepancies, but the solution has, so The QMrebind+SEEKR2 k off value for the Hsp90-ligand 37 complex deviates significantly from its experimental value and is considered an outlier. This complex is excluded from the linear fit and Kendall's tau analysis (Supplementary Figure for the line of best fit and Kendall's tau statistics, including complex 37).