A disulfide bridge is a covalent bond formed by oxidation of the thiol groups of two cysteine residues into a sulfur–sulfur linkage. It is the only common covalent crosslink in natural peptides and proteins, and it removes two hydrogen atoms, so a bridged peptide is 2 Da lighter than its reduced form — a difference visible by mass spectrometry.
Why disulfide bridges matter in peptide research
They convert a floppy chain into a constrained loop, which is often what makes receptor binding possible at all. Oxytocin and vasopressin each carry a single bridge closing a six-residue ring; somatostatin, insulin and many toxin-derived peptides depend on them entirely. A synthetic peptide supplied in reduced, unbridged form may be chemically correct by sequence and yet inactive in an assay.
Two failure routes deserve attention. Scrambling occurs when a multi-cysteine peptide folds into the wrong pairing during oxidation, giving an isomer with identical mass but different retention on HPLC. Reduction by thiol-containing buffer components can open a bridge that was correctly formed. A useful certificate of analysis states the disulfide connectivity, not merely the mass. Related: cyclic peptide and somatostatin.