Cation-pi interactions in proteins: Can simple models provide an accurate description?

It has been suggested that cation-pi interactions constitute a strong, spec ific driving force that plays a key role in molecular recognition. The impo rtance of such interactions in biological systems is explored here via two complementary approaches. The first one relies on an analysis of the associ ation of phenylalanine, tyrosine, and tryptophan with arginine and lysine i n 1718 representative protein structures, highlighting orientational prefer ences in cation-pi complexes. The second one consists of an MP2/6-311++G**/ /MP2/6-31G** ab initio investigation of the dimers formed by relevant model s of the amino acid side chains that are engaged in cation-pi interactions. The estimated induction contribution to the binding energies confirms that polarization effects are significant. The ability of commercial, two-body potential energy functions to describe cation-pi interactions accurately is also investigated, and the inclusion of correcting parameters in the force field is discussed. Put together, these results provide new insights into the nature of cation-x association in proteins.