An ab initio and data mining study on aromatic–amide interactions

The aromatic–amide interaction has been investigated by means of theoretical calculations and analyses of experimental protein structures. Ab initio calculations of the benzene–formamide model complex show that the interaction can achieve a significant stabilization energy (4.0 kcal/mol) which involves the entire amide moiety rather than only the amine and which originates mainly from dispersion and quadrupole(aromatic)–dipole(amide) electrostatic interactions. Data mining of X-ray protein structures reveals that the face-to-face orientation is the preferred configuration; more than four energetically favored aromatic(Phe)–amide interaction configurations occur in protein structures in nature, each corresponding to 1.0–4.0 kcal/mol stabilization energy. This study demonstrates that the aromatic–amide interaction is of general significance to protein structure due to both its strength and its frequent occurrence.