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. 2011 Oct 7;10(10):4505-12.
doi: 10.1021/pr200323a. Epub 2011 Sep 7.

Cycloquest: Identification of Cyclopeptides via Database Search of Their Mass Spectra Against Genome Databases

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Free PMC article

Cycloquest: Identification of Cyclopeptides via Database Search of Their Mass Spectra Against Genome Databases

Hosein Mohimani et al. J Proteome Res. .
Free PMC article

Erratum in

  • J Proteome Res. 2011 Dec 2;10(12):5575

Abstract

Hundreds of ribosomally synthesized cyclopeptides have been isolated from all domains of life, the vast majority having been reported in the last 15 years. Studies of cyclic peptides have highlighted their exceptional potential both as stable drug scaffolds and as biomedicines in their own right. Despite this, computational techniques for cyclopeptide identification are still in their infancy, with many such peptides remaining uncharacterized. Tandem mass spectrometry has occupied a niche role in cyclopeptide identification, taking over from traditional techniques such as nuclear magnetic resonance spectroscopy (NMR). MS/MS studies require only picogram quantities of peptide (compared to milligrams for NMR studies) and are applicable to complex samples, abolishing the requirement for time-consuming chromatographic purification. While database search tools such as Sequest and Mascot have become standard tools for the MS/MS identification of linear peptides, they are not applicable to cyclopeptides, due to the parent mass shift resulting from cyclization and different fragmentation patterns of cyclic peptides. In this paper, we describe the development of a novel database search methodology to aid in the identification of cyclopeptides by mass spectrometry and evaluate its utility in identifying two peptide rings from Helianthus annuus, a bacterial cannibalism factor from Bacillus subtilis, and a θ-defensin from Rhesus macaque.

Figures

Figure 1
Figure 1
Ribosomal cyclopeptides appear in all domains of life. The number of cyclopeptides sequenced in 1965-2010. The majority of known cyclopeptides have been found in plants. The data on cyclopeptides prior to 2008 have been imported from Uniprot, and the data for 2009 and 2010 have been imported from Cybase. The detail of cyclopeptides found before 1997 is shown in Table S1.
Figure 2
Figure 2
Head-to-tail cyclization versus concatenated cyclization. (A) Head to tail cyclization of SFTI-1 from within PawS1. (B) Concatenated cyclization of θ-defensin. Nine amino acid segments of two different proteins (RTD1a and RTD1b) are concatenated.
Figure 3
Figure 3
Steps of Cycloquest (for concatenated cyclopeptides such as RTD-1).
Figure 4
Figure 4
The number of decoy hits plotted against the number of identification. The number of cyclic target hits is shown in black, the number of linear decoy hits is shown in red, and the number of cyclic decoy hits is shown in blue.

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