Experimental overview of iqPIR application to cross-linked protein standards and 17-AAG treated HeLa cells. (A) Cartoon depiction of the RH and SH iqPIR cross-linkers illustrating the primary molecular features including MS-labile bonds, amine reactive groups, location of 13C isotopes (red & blue circles) and biotin affinity tag. (B) Preparation of iqPIR cross-linked standard protein samples consisting of ADH1_YEAST, ALBU_BOVIN, and MYG_HORSE mixed at various RH/SH ratios as indicated, well as an in vivo cross-linked 17-AAG treated vs vehicle (0.1% DMSO) HeLa cell sample. (C) Example total ion chromatogram representing LC–MS/MS analysis of cross-linked peptide pair samples. (D) Data analysis consisted of a Comet database search, XLinkProphet FDR estimation and filtering, quantification of relative abundance of fragment ions in the MS2 spectra and upload of data to XLinkDB.