Clustering of Aromatic Amino Acid Residues around Methionine in Proteins

Short-range, non-covalent interactions between amino acid residues determine protein structures and contribute to protein functions in diverse ways. The interactions of the thioether of methionine with the aromatic rings of tyrosine, tryptophan, and/or phenylalanine has long been discussed and such interactions are favorable on the order of 1-3 kcal mol(-1). Here, we carry out a new bioinformatics survey of known protein structures where we assay the propensity of three aromatic residues to localize around the [-CH2-S-CH3] of methionine. We term these groups 3-bridge clusters. A dataset consisting of 33,819 proteins with less than 90% sequence identity was analyzed and such clusters were found in 4093 structures (or 12% of the non-redundant dataset). All sub-classes of enzymes were represented. A 3D coordinate analysis shows that most aromatic groups localize near the CH2 and CH3 of methionine. Quantum chemical calculations support that the 3-bridge clusters involve a network of interactions that involve the Met-S, Met-CH2, Met-CH3, and the pi systems of nearby aromatic amino acid residues. Selected examples of proposed functions of 3-bridge clusters are discussed.

Automated summary

Short-range non-covalent interactions between amino acid residues play a crucial role in determining protein structures and functions. The interactions between the thioether of methionine and the aromatic rings of tyrosine, tryptophan, and/or phenylalanine are highly favorable. A new bioinformatics survey of protein structures reveals the presence of clusters formed by the localization of these aromatic residues around the methionine thioether. These clusters, known as 3-bridge clusters, show a network of interactions involving the methionine sulfur, methylene, methyl groups, and nearby aromatic residues. The findings suggest potential functional roles of 3-bridge clusters in proteins.