Experimental k off data indicate distinct residence time profiles for a series of inhibitors in the loop and helix conformations of the Hsp90 protein. Ligands 1 and 4 exhibit prolonged residence times, characterized by k off values less than 10 -4 s -1 , while lig-and 9 displays the shortest residence time with a k off value of (8.2 ± 0.5) × 10 -1 s -1 (Supplementary Table ). Unbiased MD simulations are performed for the two Hsp90-inhibitor complexes involving ligands 1 (slowest k off ) and 9 (fastest k off ) to elucidate the underlying factors contributing to discrepancies in residence times. Since these inhibitors are loop binders, direct comparisons can be made to investigate the structural and dynamic determinants governing the receptor-ligand (un)binding kinetics. Initial structures and force field parameters for the Hsp90-inhibitor complexes are obtained from the first Voronoi cell of the QMrebindreparameterized SEEKR2 milestones. A total of 10 µs of MD simulations are run for each receptor-inhibitor complex at 300 K with a 2 fs timestep and a nonbonded cutoff distance of 10 Å using the Amber20 MD engine 149 . Simulation trajectories are analyzed using the CPPTRAJ module of the Amber 20 package .