Updated project metadata. We report the combination of protein-denaturation stability principles with quantitative cross-linking mass spectrometry using isobaric quantitative protein interaction reporter technologies. This method enables the evaluation of ligand-induced protein engagement through analysis of cross-link relative ratios across chemical denaturation. We found ligand-stabilized cross-linked lysine pairs in bovine serum albumin (BSA) and ligand bilirubin map to known binding sites Sudlow Site I and subdomain IB.