A number of αA‐crystallin mutants are associated with hereditary cataract including cysteine substitution at arginine 49. We report the formation of affinity‐driven disulfide bonds in the interaction of αA‐R49C with βB1‐crystallin. To mimic cysteine thiolation in the lens, βB1‐crystallin was modified by a bimane probe through a disulfide linkage. Our data suggest a mechanism whereby a transient disulfide bond occurs between αA‐ and βB1‐crystallin followed by a disulfide exchange with cysteine 49 of a neighboring αA‐crystallin subunit. This is the first investigation of disulfide bonds in the confine of the chaperone/substrate complex where reaction rates are favored by orders of magnitude. Covalent protein cross‐links are a hallmark of age‐related cataract and may be a factor in its inherited form.