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.

A graphite-adsorbed tricarbonylrhenium(i) terpyridine complex supports CO2 reduction electrocatalysis over a wide range of pH values.

The amino acid residue methionine (Met) is often thought of as a ligand in redox metalloproteins, but its roles and interactions can be much more diverse.

Redox-active amino acid residues are at the heart of biological electrontransfer reactions. They play important roles in natural protein functions and are implicated in disease states (e.g., oxidative-stress-associated disorders). Tryptophan (Trp) is one such redox-active amino acid residue, and it has long been known to serve a functional role in proteins. Broadly speaking, there is still much to learn about the local features that make some Trp redox active and others inactive. Herein, we describe a new protein model system where we investigate how a methionine (Met) residue proximal to a redox-active Trp affects its reactivity and spectroscopy. We use an artificial variant of azurin from Pseudomonas aeruginosa to produce these models. We employ a series of UV−visible spectroscopy, electrochemistry, electron paramagnetic resonance, and density functional theory experiments to demonstrate the effect that placing Met near Trp radicals has in the context of redox proteins. The introduction of Met proximal to Trp lowers its reduction potential by ca. 30 mV and causes clear shifts in the optical spectra of the corresponding radicals. While the effect may be small, it is significant enough to be a way for natural systems to tune Trp reactivity.