In Fig S13 , we plot the RMSD of the ligand heavy atoms relative to the crystal structure and color each time point by assigning it to the macrostate which minimizes the RMSD. Specifically, we compute the ligand heavy atom RMSD to the 50 representative microstates (simulation frames) belonging to each macrostate; then, assign it to the macrostate which minimizes the RMSD. We can then compute the populations or amount of simulation time spent within each binding mode by counting how many frames fall within each binding mode (Fig. ).