A novel approach for untargeted post-translational modification identification using integer linear optimization and tandem mass spectrometry

Richard C. Baliban, Peter A. DiMaggio, Mariana D. Plazas-Mayorca, Nicolas L. Young, Benjamin A. Garcia, Christodoulos A. Floudas

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

A novel algorithm, PILOT-PTM, has been developed for the untargeted identification of post-translational modifications (PTMs) on a template sequence. The algorithm consists of an analysis of an MS/MS spectrum via an integer linear optimization model to output a rank-ordered list of PTMs that best match the experimental data. Each MS/MS spectrum is analyzed by a preprocessing algorithm to reduce spectral noise and label potential complimentary, offset, isotope, and multiply charged peaks. Postprocessing of the rank-ordered list from the integer linear optimization model will resolve fragment mass errors and will reorder the list of PTMs based on the cross-correlation between the experimental and theoretical MS/MS spectrum. PILOT-PTM is instrument-independent, capable of handling multiple fragmentation technologies, and can address the universe of PTMs for every amino acid on the template sequence. The various features of PILOT-PTM are presented, and it is tested on several modified and unmodified data sets including chemically synthesized phosphopeptides, histone H3-(1-50) polypeptides, histone H3-(1-50) tryptic fragments, and peptides generated from proteins extracted from chromatin-enriched fractions. The data sets consist of spectra derived from fragmentation via collision-induced dissociation, electron transfer dissociation, and electron capture dissociation. The capability of PILOT-PTM is then benchmarked using five state-of-the-art methods, InsPecT, Virtual Expert Mass Spectrometrist (VEMS), Modi, Mascot, and X!Tandem. PILOT-PTM demonstrates superior accuracy on both the small and large scale proteome experiments. A protocol is finally developed for the analysis of a complete LC-MS/MS scan using template sequences generated from SEQUEST and is demonstrated on over 270,000 MS/MS spectra collected from a total chromatin digest.

Original languageEnglish
Pages (from-to)764-779
Number of pages16
JournalMolecular and Cellular Proteomics
Volume9
Issue number5
DOIs
StatePublished - May 2010

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