Metal Ligand Aromatic Cation–π Interactions in Metalloproteins: Ligands Coordinated to Metal Interact with Aromatic Residues

Abstract

Cation-pi 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-pi interaction in metalloproteins; namely interaction between ligands coordinated to a metal cation--which gain positive charge from the metal--and aromatic groups in amino acid side chains. Investigation of crystal structures of metalloproteins in the Protein Data Bank (PDB) has revealed that there exist quite a number of metalloproteins in which aromatic rings of phenylalanine, tyrosine, and tryptophan are situated close to a metal center interacting with coordinated ligands. Among these ligands are amino acids such as asparagine, aspartate, glutamate, histidine, and threonine, but also water and substrates like ethanol. These interactions play a role in the stability and conformation of metalloproteins, and in some cases may also be directly involved in the mechanism of enzymatic reactions, which occur at the metal center. For the enzyme superoxide dismutase, we used quantum chemical computation to calculate that Trp163 has an interaction energy of 10.09 kcal mol(-1) with the ligands coordinated to iron.

Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family

“…Aromatic residues are known to coordinate cations and metal ions, such as Mg 2ϩ and Mn 2ϩ , through cation-⌸ interactions (29). Although long known for their structural role, these interactions have recently been revisited regarding their catalytic potential (30). Thus, for example, the endonuclease EndN was shown to employ Tyr and His residues to coordinate a catalytic Zn 2ϩ (31).…”

Intramolecular Metal Ligand Aromatic Cation−π Interactions in Crystal Structures of Transition Metal Complexes

“…Hence, it is not possible to observe a regular correlation between the interaction distances and the amount of positive charge on the hydrogen atom, as is possible with metalloproteins where MLACπ interactions are not as constrained by steric influences. [23] It is interesting to point out that from spectra of the trans,mer-[IrCl 2 (NH 3 )(PMe 2 Ph) 3 ] ϩ complex in solution, it is evident that there is rapid rotation about the IrϪP bonds, [45] which means that there are no MLACπ interactions in solution.…”

“…[24,25] Metal ligand aromatic cationϪπ (MLACπ) interactions in metalloproteins were discovered by searching crystal structures of metalloproteins from the Protein Data Bank (PDB). [23] These data reveal that there are quite a number of metalloproteins, where aromatic rings from phenylalanine, tyrosine, and tryptophan are close to a metal center, interacting with coordinated ligands. Among these ligands are amino acids like asparagine, aspartate, glutamate, histidine, and threonine, but also substrates like water and ethanol.…”

Importance of lone pair interactions/redistribution in hard and soft ligands within the active site of alcohol dehydrogenase Zn-metalloenzyme: Insights from electron localization function

“…A Phe residue has a stacking interaction with ethanol and could thus further contribute to stabilization by an indirect cation-¥interaction with Zn(II) (Li et al, 1994;de Courcy et al, 2008). Such a motif has been reviewed by Zaric et al (Zaric et al, 2000). We have recently quantified the contribution of Phe to the overall stability of the binding site and the weights of first-order, second-order, and dispersion/correlation.…”