Fig. 14.

Ligand-solvent and receptor(5JXG)-solvent hydrogen bond counts over the 53-ps BOS-318 iMD trajectory demonstrating partial dehydration of the ligand as it entered the side-channel of 5JXG. Primarily solution-phase water molecules located within 5.0 Å of the ligand at t = 0 ps are rendered as yellow spheres. Primarily protein-associated water molecules located within 5.0 Å of the ligand at t = 53 ps are rendered as magenta-colored spheres. All other water molecules and ions have been hidden for clarity. The majority of the solution-phase water associated with the ligand at t = 0 ps were stripped away from the ligand during the intMD trajectory. The ligand was partially rehydrated following docking into the catalytic cleft. Moreover, two trends were apparent: (1) Water molecules (yellow) that dissociated from the ligand during side-channel entry became dispersed as they diffused into the bulk solvent phase, suggesting an increase in system entropy; and (2) Water molecules that ultimately became associated with the bound ligand (magenta) gradually increased in density (around the bound ligand) compared to their initial t = 0 state, presumably due to attractive interactions with the ligand. Re-organization of water molecules around the ligand suggests a possible decrease in system entropy. These observations are consonant with the hydrogen-bonding trends shown in the graph (lower panel), which is color-coded according to the sequence of intMD docking events, including: (1) Initial ligand de-solvation phase (green shading); (2) Ligand binding in the cleft (yellow shading); (3) Post-iMD equilibration phase (gray shading); and (4) Ligand re-hydration (blue shading).