Noncovalent S–S···S–S Interactions between Disulfide Bridges in Proteins: A Combined PDB Analysis and Quantum Chemical Study

Disulfide bonds play essential structural and regulatory roles in proteins; however, the noncovalent interactions (NCIs) between these disulfide motifs remain largely unexplored. In this work, we investigate the nature of S-S···S-S interactions using a combined Protein Data Bank (PDB) survey and quantum chemical calculations. Statistical analyses of protein crystal structures reveal the preferred intermolecular sulfur-sulfur distances of approximately 3.6 Å and 4.8 Å, suggesting the presence of stabilizing NCIs between disulfide bridges. To elucidate the intrinsic features of these interactions, dimethyl disulfide (DMDS) was employed as a model system. Computational analysis of multiple dimer conformers reveals that for arrangements with intermolecular sulfur-sulfur distance greater than 3.6 Å (sum of van der Waals radii of two sulfurs), stability is primarily driven by C-H···S hydrogen bonds. In contrast, for conformers with shorter intermolecular sulfur-sulfur distances (⩽3.6 Å), stabilization arises from a cooperative interplay between C-H···S hydrogen bonds and directional S···S chalcogen bonds. This study presents the first report of S···S chalcogen bonding between disulfide bonds, highlighting its potential role in biochemical architecture.