Conformational Preferences of π-π stacking between ligand and protein, Analysis derived from Crystal Structure Data

π-π interaction is a direct attractive non-covalent interaction between aromatic moieties, which plays an important role in DNA stabilization, drug intercalation, etc. Aromatic rings interact through several different conformations including face-to-face, T-shaped and offset stacked conformation. Previous quantum calculations indicated that T-shaped and offset stacked conformations are preferred for their smaller electron repulsions. However, substitution group on aromatic ring could have a great impact on π-π interaction by changing electron repulsion force between two rings. To investigate π-π interaction between ligand and aromatic side chain of protein, Brookhaven Protein Data Bank had been analyzed. We extracted isolated dimer pairs with the aim of excluding multiple π-π stacking effects which may be different from single interaction situation. We found that T-shaped conformation is prevalent among aromatic interaction between phenyl ring of ligand and protein, which corresponds with the phenomenon of Phe-Phe interactions in small peptide. Specifically, for non-substitution model, both Phe-Phe and Phenyl-Phe exhibit a favored T-shaped conformation whose dihedral angle is around 50°-70° and centroid distance is between 5.0 A and 5.6 A. However, it could be changed by substituent effect. The hydroxyl group could contact in the case of Tyr-Tyr pairs, while they point away from phenyl plane in Phe-Tyr pairs.