From the trajectories, first, we extracted all frames where 5b is bound to Hsp90 (no-fit RMSD of 5b ≤ 1.5 Å to the previous frame after superimposing Hsp90). Mapping the probability density of occurrence of 5b onto the surface of Hsp90 (Figure ) revealed two main binding regions: one in the C-terminal helix interface (Figure , green), where binding occurred in 10 out of the 40 replicas, and another in a cleft between the CTD and middle domain (Figure , blue), where binding occurred in 6 out of 40 replicas. In the latter case, an area of high density with the shape of 5b is observed (Figure , light blue), which resulted from a single trajectory. This indicates that the ligand was kinetically trapped in this one case, although the position is thermodynamically not favorable. By contrast, the densities in the C-terminal interface are more ambiguously shaped, indicating that, while binding there is favorable, the ligand can still explore multiple binding modes, which are also seen to interchange.