Technological Innovation and Resources
Fast Multi-blind Modification Search through Tandem Mass Spectrometry*
Multi-blind Identification of PTMs

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With great biological interest in post-translational modifications (PTMs), various approaches have been introduced to identify PTMs using MS/MS. Recent developments for PTM identification have focused on an unrestrictive approach that searches MS/MS spectra for all known and possibly even unknown types of PTMs at once. However, the resulting expanded search space requires much longer search time and also increases the number of false positives (incorrect identifications) and false negatives (missed true identifications), thus creating a bottleneck in high throughput analysis. Here we introduce MODa, a novel “multi-blind” spectral alignment algorithm that allows for fast unrestrictive PTM searches with no limitation on the number of modifications per peptide while featuring over an order of magnitude speedup in relation to existing approaches. We demonstrate the sensitivity of MODa on human shotgun proteomics data where it reveals multiple mutations, a wide range of modifications (including glycosylation), and evidence for several putative novel modifications. Based on the reported findings, we argue that the efficiency and sensitivity of MODa make it the first unrestrictive search tool with the potential to fully replace conventional restrictive identification of proteomics mass spectrometry data.

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*

The work described in this paper has been conducted while S. Na and E. Paek were at University of Seoul. This work was supported by 21C Frontier Functional Proteomics Project Grant FPR08-A1-020 from the Korean Ministry of Education, Science & Technology (MEST); by National Research Foundation of Korea Grant 2011-0006244 funded by the Korea Government; by the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University; and by the 2010 Research Fund of the University of Seoul. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article contains supplemental material.

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Supported by Brain Korea 21 (BK21) Project and Seoul Science Fellowship.

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Supported in part by National Institutes of Health Grant 1-P41-RR024851 from the National Center for Research Resources.