Fig. 4

Simulation of the protein and ligand hydration effects. a Relation between the computed desolvation free energy of the inhibitors (see Methods section) and their measured binding entropy in ITC experiments. Compounds assigned as loop-binders are colored black and compounds assigned as helix-binders are colored red. Error bars show the root mean squared error of 3D-RISM predictions against experiment (RMSE=5.4 kJ mol⁻¹ as reported in ref. ⁵⁰). Black and red dashed lines indicate the average values of the desolvation energy and binding entropy for loop- and helix-binders, and the arrows show the corresponding differences between loop- and helix-binding compounds, as observed in experiment (gray) and in computations (light red). b, c Conserved water sites observed in loop-in (b) and helical (c) crystal structures (listed in Supplementary Table 5). The degree of conservation is visualized by increasing size and color; only water sites within 0.8 nm of N106 are shown. In the insets, water sites predicted by GIST⁶⁸ are depicted by blue mesh iso-surfaces at a water density value twice that of bulk water; the oxygen atoms of the crystallographic water sites are represented by red spheres; red arrows indicate the positions of stable water sites predicted by 3D-RISM simulations⁶⁶ (for details, see Supplementary Information)