Chemical cross-linking and mass spectrometry have recently been shown to constitute a powerful tool to study protein-protein interactions and to help elucidate the structure of large protein complexes. However, computational methods to interpret the complex MS/MS spectra from linked peptides are still in their infancy, thus making the high-throughput application of this approach largely impractical. Due to the lack of large annotated datasets, most current approaches do not capture the specific fragmentation patterns of linked peptides and therefore are not optimal for identification of cross-linked peptides. Here we propose a generic approach to address this problem and demonstrate it using… Read more »
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Detection of complex post-translational modifications (PTMs) remains a challenging open problem in proteomics. Simple PTMs (e.g. methylation, deamidation etc.) can be readily identified in tandem mass spectrometry (MS/MS) by considering characteristic mass shifts in peptide fragment ions. However, more complex PTMs such as glycosylation and small ubiquitin-like modification (SUMOylation) present a more difficult problem because the modification changes the fragmentation pattern of the substrate peptide substantially, making current database search methods not suitable to identify MS/MS spectra from these modified peptides. We propose a novel approach to enable the expedited development of new algorithms for any types of PTM peptide… Read more »
Tremolo is a spectral library search tool that leverages the Spectral Library Generating Function (SLGF) concept to identify spectrum-spectrum matches (SSMs). The SLGF models the variability of replicate spectra as compared to reference library spectra. Given a similarity function (in our case cosine), SLGF yields an expected score distribution for each reference library spectrum. Tremolo is able to assign p-values to SSMs and it has been shown to increase the sensitivity of spectral library searches.
Most computational approaches makes the assumption that each MS/MS spectrum comes from one peptide while there are numerous situations where one MS/MS spectrum can contain fragment ions corresponding to two or more peptides. Examples include mixture spectra from co-eluting peptides in complex samples, spectra generated from data-independent acquisition methods and spectra from peptides with complex PTMs and cross-linked peptides. We propose a new database search tool (MixDB) that is able to identify mixture MS/MS spectra from more than one peptide. We show that peptides can be reliably identified with up to 95% accuracy from mixture spectra while considering only a… Read more »
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