SEEKR2 simulations employing QMrebind-reparameterized force fields outperformed the SEEKR2 simulations employing the generic force fields in more accurately estimating the unbinding rates for all eight Hsp90-inhibitor complexes (Figure ). Both force fields within the SEEKR2 framework provided closeto-experimental k off rates for the Hsp90-ligand 9 complex, with the QMrebind-reparameterized force field slightly outperforming the generic one (Supplementary Table ). For the rest of the seven complexes involving ligands 1, 3, 4, 22, 31, 59, and 67, QMrebind-reparameterized SEEKR2 simulations significantly outperformed generic force field SEEKR2 simulations in estimating the k off rates. However, for the Hsp90-ligand 22 and 31 complexes, neither of the methods could estimate the k off rates within an order of magnitude to the experimental values, with the QMrebind-reparameterized force field simulations performing better than the generic force field. In the cases of complexes 1 and 4, the experimental k off values were only known to be less than 1 × 10 -4 s -1 , and unbinding rates obtained with QMre-bind+SEEKR2 and SEEKR2 methods seem reasonable within the margin of uncertainty. To further validate the consistent accuracy of QMrebind-reparameterized SEEKR2 simulations in estimating receptor-ligand unbinding rates, an additional set of nine Hsp90inhibitor complexes is selected. These inhibitors encompassed a diverse range of k off rates and scaffold diversity (Figure ), allowing us to thoroughly assess the accuracy and robustness of the QMrebind-reparameterization method across a broader spectrum of estimating k off rates for receptor-ligand interactions. Unbinding rate estimates for the eight Hsp90-inhibitor complexes were substantially improved by the use of QMrebind, so that, while they do not match within experimental or theoretical error margins, they often fall within the single order of magnitude criteria for success and in almost all cases, at least within 2