Directional preferences of intermolecular contacts to hydrophobic groups.

Analysis of data from the IsoStar library shows that many hydrophobic groups exhibit strikingly strong directional preferences in their intermolecular interactions. Specific directional interactions may occur because of the large quadrupole moments of many aromatic ring systems, the residual electropositive charge on most carbon-bound H atoms and the effects of polarization on soft hetero-ring atoms such as sulfur. In consequence, the binding of a hydrophobic group to a hydrophobic protein cavity is not simply a matter of matching complementary shapes. Directional preferences of nonbonded contacts to hydrophobic groups may need to be taken into account in parameterizing the next generation of protein-ligand docking programs.