In Figure we report the time record of 12 juxtaposed replicates of standard MD simulations each lasting 24 ns. The five magenta-highlighted replicates indicate independent 24 ns MD simulations where the secondary pose was never observed. The secondary pose was sampled 10 times in the total 288 ns time span of standard MD replicates, with a probability of 7% (as in HREM). In the bottom plot of Figure , we show a zooming of the 10th MD replicate where the pose switch was observed. Note that the effective duration of this rare event was less than 200 ps, despite the fact that ligand must rotate by 60 • around the axis perpendicular to the phenyl ring, breaking an H-bond and forming a new one (see Figure ), resulting in an overall shift of the ligand COM of nearly 3 Å. Again, we are dealing also in this case with a rare event that occurs on a fast time-scale. In Figure we finally compare the probability distribution (and the associated PMF) of the poses of the ODR ligand in the BRD4(I) complex obtained in HREM and using MD. Inspection of Figure shows that standard and adaptive HREM produces essentially the same probability profile and PMF. This probability and PMF can only be recovered using 12 replicates of MD (for a total of 288 ns), while a simple 24 ns vanilla simulation (first of the 12 replicates in Figure ) is missing completely the sampling of the secondary pose.