GIST grids were generated using the CPPtraj tool from Am-berTools 19 by processing MD trajectories with a grid spacing of 0.5 x 0.5 x 0.5 Å. From MD trajectories, 30,000 frames (10,000 x 3 replicates) were extracted and analyzed for fa10, fkb1a, hsp90a, ital, kith, and pgh2 systems. Due to convergence issues, the GIST analyses for hivpr, nram, fabp4 and streptavidin systems were extended to include 100,000 frames (Fig. , S22, S16, S24). The grids were manipulated using the Python package gridData from MDAnalysis Hydration sites.