Metal ligand aromatic cation-pi interactions in metalloproteins: Ligands coordinated to metal interact with aromatic residues

Cation-se interactions between aromatic residues and cationic amino groups in side chains and have been recognized as noncovalent bonding interactions relevant for molecular recognition and for stabilization and definition of the native structure of proteins. We propose a novel type of cation-x inte raction in metalloproteins; namely interaction between ligands coordinated to a metal cation-which gain positive charge from the metal-and aromatic gr oups in amino acid side chains. Investigation of crystal structures of meta lloproteins in the Protein Data Bank (PDB) has revealed that there exist qu ite a number of metalloproteins in which aromatic rings of phenylalanine, t yrosine, and tryptophan are situated close to a metal center interacting wi th coordinated ligands. Among these ligands are amino acids such as asparag ine, aspartate, glutamate, histidine, and threonine, but also water and sub strates like ethanol. These interactions play a role in the stability and c onformation of metalloproteins, and in some cases may also be directly invo lved in the mechanism of enzymatic reactions, which occur at the metal cent er. For the enzyme superoxide dismutase, we used quantum chemical computati on to calculate that Trp163 has an interaction energy of 10.09 kcal mol(-1) with the ligands coordinated to iron.