Fig. 1.

Hydrophobic ligand–pocket model. (Left) MD snapshot of pocketed wall and ligand (green sphere) in explicit water. (Right) Coordinate system. A hemispherical, purely nonpolar pocket with a ligand-accessible radius of Å embedded in a planar wall is in contact with explicit water at normal conditions. The ligand is modeled by a hydrophobic methane sphere and is restrained to the symmetry axis z. In the “umbrella runs” the ligand is additionally constrained to position by a harmonic potential.