A survey of methionine-aromatic interaction geometries in the oxidoreductase class of enzymes: What could Met-aromatic interactions be doing near metal sites?

Abstract

Redox reactions of the aromatic amino acids tyrosine (Tyr) and tryptophan (Trp) are crucial for the biological functions of many metalloproteins. An important question is how biological systems can use the protein environment to move electrons through proteins in a controlled manner. Methionine (Met)-aromatic interactions are common in proteins, but little is known about redox reactions of such motifs. Here, we explore methionine sulfur-aromatic interactions in the oxidoreductase (EC 1) class of proteins and their proximity to metal sites. We also propose a new metric for classifying Met-aromatic interactions called “interaction order.” Over 12,000 protein structures from the Protein Data Bank were analyzed. A linear algebraic heuristic was used to classify the interaction of Met‑sulfur with tyrosine, tryptophan, and phenylalanine. We found that 83% of oxidoreductase proteins contained aromatic interactions meeting our criteria, with a preferential angle of about 60° between Met‑sulfur lone pairs and aromatic planes. A total of 41% of Met-aromatic interactions meeting our criteria were found to be within 20 Å of a metal site, and 6% were found within 10 Å. A surprising number of “bridging” interactions, involving two aromatic residues and one Met also were identified. Finally, selected examples of potentially important Met-aromatic redox motifs are outlined. On the basis of our results, we suggest that Met-aromatic interactions should be considered as mediators of electron transfer reactions, as well as their more widely recognized roles as structural motifs.