PDB and topology files for the Hsp90-ligand complexes are obtained from the original study 137 . Before initiating the QMrebind reparameterization process, structure files are subjected to energy minimization (using only MM) to ensure the stability and optimal conformation of the receptor-ligand complexes. In the reparameterization process, the Hsp90-inhibitor complexes are partitioned into three regions, the high-level QM region, the lowlevel QM2 region, and the MM region. The inhibitors comprise the QM region, where second-order Møller-Plesset perturbation (MP2) theory is implemented with the cc-pVTZ basis set. The binding site residues having any atoms within a cut-off distance of 5 Å comprise the QM2 region, where the semi-empirical tightbinding method, GFN2-XTB, is employed (refer to Supplementary Table for an exhaustive list of binding site residues for Hsp90-inhibitor complexes). The rest of the protein comprises the MM region. CVs are defined based on the distance between the COM of the inhibitor and the α-carbon atoms of the residues at the binding site. For each of the Hsp90-inhibitor complexes, 20 CV-based milestones are defined as concentric spheres and are located at distances of 1.00, 1. Starting structures for SEEKR2 simulations are obtained using the SMD simulations, where a moving harmonic restraint of 30,000 kJ mol -1 nm -2 is applied over the course of 100 ns. A single set of SEEKR2 simulations with the reparameterized and generic force field parameters are run with the same milestone spacings for all the complexes. A total of 400 ns of MD simulations are run within each Voronoi cell, totaling a simulation time of 8 µs for 20 Voronoi cells. For a subset of eight of the HSP90 inhibitors, the performance of QMrebind+SEEKR2 simulations is evaluated by comparing it with SEEKR2 simulations with generic force fields with the same simulation time, milestone spacings, and collective variable definitions for each of the Hsp90-inhibitor complexes.