Clustering of Aromatic Amino Acid Residues around Methionine in Proteins

Abstract

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 π systems of nearby aromatic amino acid residues. Selected examples of proposed functions of 3-bridge clusters are discussed.

Proximal Methionine Amino Acid Residue Affects the Properties of Redox-Active Tryptophan in an Artificial Model Protein

“…The local structures (microenvironments) that house amino acids can substantially influence their reactivity. , Examples include the long-lived Tyr radical in Type II ribonucleotide reductase, , the hydrogen-bonded Tyr residue in photosystem II (Tyr z ), , and the hydrogen-bonded Trp indole in lignin/versatile peroxidases. , Herein, we are concerned with Trp and some examples of redox-active Trp and its microenvironments are shown in Figure . − Work from our research group, − and from others, − has shown that Trp amino acid residues are regularly found near Met in proteins from diverse organisms. There also are examples where the sites of Met–Trp interactions are redox active, with the best known example found in cytochrome c peroxidase. , These observations motivated the production and investigation of the protein models here, where Met is strategically introduced proximal to a redox-active Trp.…”

On the roles of methionine and the importance of its microenvironments in redox metalloproteins

“…More recently, we described interactions where three aromatic groups localized around a single Met. 31 While the incidence of these interactions is lower than the bridging interactions noted above, these Met-aromatic "three-bridges" can be found in all classes of proteins. In particular, we identified several instances of these interactions near the sites of heme enzymes involved in oxygen and peroxide chemistry (e.g., cytochrome c peroxidase, catalase, and prostaglandin H synthase).…”

“…We recently described bioinformatics surveys of Met-sulphur-aromatic (Met(S)-aromatic) interactions. 29–31 In the first, the locations of Met(S)-aromatic interactions were assessed in metalloproteins. 29 That investigation revealed several noteworthy features.…”

A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer

“…The highly polarizable sulfur atom of the Met side chain can form with other aromatic side chains stronger interactions than Phe. 70,71 Interestingly, these new mutations do not affect the decrease in forskolin-induced cAMP in a significant manner, thus suggesting they do not block the entrance of the JWH-133 ligand probably due to the higher flexibility of Met relative to Phe. Our experimental results point out that the highly stable aromatic cluster between Phe91 2.61 , Phe94 2.64 , His95 2.65 , and Phe282 7.36 (in the Ala282 7.36 Phe mutation) blocks the entrance of JWH-133 to the orthosteric binding site.…”