Cl-π interactions in protein-ligand complexes

During systematic analysis of nonbonded contacts in protein-ligand complexes derived from crystal structures in the Protein Data Bank, Cl-pi interactions have been found, not only in the well-documented serine proteases but also, to a lesser extent, in other proteins. From geometric analysis of such Cl-pi interactions in the crystal structures, two distinct geometries were found: the edge-on'' approach of a Cl atom to a ring atom or C-C bond and the face-on'' approach toward the ring centroid with an average interatomic distance of 3.6 angstrom. High-level ab initio calculations using benzene-chlorohydro-carbon model systems elucidated that the calculated Cl-pi interaction energy is -2.01 kcal/mol, and the dispersion force is the major source of attraction. We also discussed the geometric flexibility in Cl-pi interactions and a relationship between the intensity of the pi density in an aromatic ring and the interaction position of the Cl atom.