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On-line liquid chromatography neutral loss-triggered electron transfer dissociationmass spectrometry for the targeted analysis of citrullinated peptides.

Citrullination is a post-translational modification of proteins which deiminates arginine, increasing the mass by 0.98 Da. Protein citrullination is a known biomarker for multiple sclerosis and a potential biomarker for rheumatoid arthritis. Collision-induced dissociation (CID) tandem mass spectrometry of citrullinated peptides produces a dominant neutral loss of isocyanic acid (HNCO, -43 Da) from the deiminated arginine amino acid side-chain. Here we show that the loss of isocyanic acid in CID can be used as a trigger for targeted analysis by supplemental activation electron transfer dissociation (saETD). Unlike CID, post-translational modifications (PTMs) are retained on peptide backbone fragments produced by saETD, improving the confidence in assignment of both peptide sequence and PTM site. The method is demonstrated for four synthetic peptides spiked into complex trypsin-digested saliva samples and a commercial six protein tryptic mixture. In contrast to CID alone, the neutral-loss triggered ETD approach results in high confidence identification of three of the four peptides, including an unexpected disulfide-bound dimer, and zero false positives.