Fig. 21.

[A] Reduction of ligand-solvent hydrogen bonding and increase in furin-solvent hydrogen bonding over the course of the 132-ps Mod23 iMD side-channel trajectory. The loss of ligand-solvent hydrogen bonds indicates that Mod23 became partially de-solvated as it entered the side channel and docked in the furin catalytic cleft. [B] Image frame captures from the intMD docking simulation. Water molecules located within 5.0 Å from the ligand at t = 0 ps are rendered as yellow ball-and-cylinders. Water molecules located within 5.0 Å from the ligand at t = 132 ps are rendered as magenta-colored ball-and-cylinders. Two trends are evident: (1) Dehydration of the ligand, i.e., loss of solvent-phase water molecules from the original 5.0-Å water shell (yellow) as the ligand entered into and transited the furin side channel; and (2) Ligand re-hydration and densification primarily by solution-phase water molecules (magenta) as docking proceeded. Note that water molecules and ions outside of the 5.0-Å drug solvent shells have been hidden for clarity.