Sulfur-Aromatic Interactions in Protein Chemistry

Sulfur–aromatic interactions arise from favourable contacts between the partially positive sulphur atom of methionine or cysteine side chains and the electron-rich π-systems of aromatic residues such as phenylalanine, tyrosine and tryptophan. With typical interaction energies in the range of 1–3 kcal mol⁻¹, these noncovalent forces combine electrostatic, van der Waals and dispersion contributions. Structural surveys show recurrent motifs in enzyme active sites, hydrophobic cores and protein–protein interfaces, where sulphur–aromatic contacts stabilise tertiary folds, tune dynamic allostery and modulate ligand recognition. Quantum chemical analyses highlight the role of sulphur polarizability and orientation dependence, while mutagenesis and biophysical experiments quantify their contributions to thermal stability and binding affinity. Harnessing these interactions has proven valuable in protein engineering, where introduction of targeted sulphur–aromatic pairs can enhance thermostability or catalytic efficiency, and in drug design, where aromatic scaffolds engage cysteine residues in selective binding pockets. Advances in computational modelling and high-resolution spectroscopy continue to refine our understanding, offering routes to exploit sulphur–aromatic interactions in synthetic biology and therapeutic development.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Sulfur-Aromatic Interactions in Protein Chemistry publication trend

The graph below shows the total number of articles in sulfur-aromatic interactions in protein chemistry across all publications each year (not limited to Nature Index journals).

Technical terms

Sulfur–aromatic interaction: A noncovalent attraction between a sulphur atom in a methionine or cysteine side chain and the π-electron cloud of an aromatic amino acid ring.

π-system: The delocalised cloud of π-electrons above and below the plane of an aromatic ring contributing to noncovalent interactions.

Thioether: The functional group in methionine consisting of a sulphur atom bonded to two alkyl groups (–CH₂–S–CH₃).

3-bridge cluster: A structural motif in which three aromatic side chains surround and interact with the thioether and adjacent methylene groups of a single methionine residue.

β-grasp fold: A common protein fold characterised by a β-sheet “grasping” an α-helix, often found in ubiquitin and ubiquitin-like modifiers such as SUMO.

References

1. Clustering of Aromatic Amino Acid Residues around Methionine in Proteins. Biomolecules (2021).
2. An “up” oriented methionine-aromatic structural motif in SUMO is critical for its stability and activity. Journal of Biological Chemistry (2021).