π-Stacking Interactions

Abstract

A representative set of high resolution x-ray crystal structures of nonhomologous proteins have been exam- ined to determine the preferred positions and orienta- tions of noncovalent interactions between the aromatic side chains of the amino acids phenylalanine, tyrosine, histidine, and tryptophan. To study the primary inter- actions between aromatic amino acids, care has been taken to examine only isolated pairs (dimers) of amino acids because trimers and higher order clusters of aro- matic amino acids behave differently than their dimer counterparts. We find that pairs (dimers) of aromatic side chain amino acids preferentially align their respec- tive aromatic rings in an off-centered parallel orienta- tion. Further, we find that this parallel-displaced struc- ture is 0.5–0.75 kcal/mol more stable than a T-shaped structure for phenylalanine interactions and 1 kcal/mol more stable than a T-shaped structure for the full set of aromatic side chain amino acids. This experimentally determined structure and energy difference is consist- ent with ab initio and molecular mechanics calculations of benzene dimer, however, the results are not in agree- ment with previously published analyses of aromatic amino acids in proteins. The preferred orientation is referred to as parallel displaced Pi-stacking.