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Using dissociation energies to predict observability of b- and y-peaks in mass spectra of short peptides.

ABSTRACT: RATIONALE:Peptide identification reliability can be improved by excluding from analysis those m/z peaks of candidate peptides which cannot be observed in practice due to various physical, chemical or thermodynamic considerations. We propose using dissociation energies (as opposed to proton affinities) as a predictor of observability of different m/z peaks in spectra of short peptides. METHODS:Mass spectra of the tetrapeptides AAAA, AAFA, AAVA, AFAA, AVAA, AFFA, and AVVA were measured in the collision-induced dissociation (CID) activation mode on a grid of activation times 0.05 to 100 ms and normalized collision energy 10 to 35%. The lowest energy geometries and vibrational spectra were calculated for the precursor ions and their charged and neutral fragments using density functional theory (DFT) at the TPSS/6-31G(d,p) level. Dissociation energies were calculated for all fragmentation channels leading to b- or y-fragments. RESULTS:It is demonstrated that m/z peaks observed in the mass spectra correspond to the fragmentation channels with the lowest dissociation energies. Using 50 kcal/mol as the cut-off value of dissociation energy, it was predicted that 28 out of 42 possible peaks in the b- and y-series of the seven tetrapeptides can be observed in mass spectra. In the experiments, 26 b- or y-peaks were observed, all of which are among the 28 predicted ones. CONCLUSIONS:The use of dissociation energies generalizes the use of proton affinities for semi-quantitative predictions of relative intensities of different m/z peaks of short peptides. Further advances in this direction will pave the way for reliable quantitative predictions and, hence, for a significant improvement in robustness and accuracy of peptide and protein identification tools.

SUBMITTER: Obolensky OI

PROVIDER: S-EPMC3468955 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Using dissociation energies to predict observability of b- and y-peaks in mass spectra of short peptides.

Obolensky O I OI Wu Wells W WW Shen Rong-Fong RF Yu Yi-Kuo YK

Rapid communications in mass spectrometry : RCM 20120401 8

<h4>Rationale</h4>Peptide identification reliability can be improved by excluding from analysis those m/z peaks of candidate peptides which cannot be observed in practice due to various physical, chemical or thermodynamic considerations. We propose using dissociation energies (as opposed to proton affinities) as a predictor of observability of different m/z peaks in spectra of short peptides.<h4>Methods</h4>Mass spectra of the tetrapeptides AAAA, AAFA, AAVA, AFAA, AVAA, AFFA, and AVVA were measu ...[more]

PMID: 22396027

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Project description:Natural and non-natural cyclic peptides are a crucial component in drug discovery programs because of their considerable pharmaceutical properties. Cyclosporin, microcystins, and nodularins are all notable pharmacologically important cyclic peptides. Because these biologically active peptides are often biosynthesized nonribosomally, they often contain nonstandard amino acids, thus increasing the complexity of the resulting tandem mass spectrometry data. In addition, because of the cyclic nature, the fragmentation patterns of many of these peptides showed much higher complexity when compared to related counterparts. Therefore, at the present time it is still difficult to annotate cyclic peptides MS/MS spectra. In this current work, an annotation program was developed for the annotation and characterization of tandem mass spectra obtained from cyclic peptides. This program, which we call MS-CPA is available as a web tool (http://lol.ucsd.edu/ms-cpa_v1/Input.py). Using this program, we have successfully annotated the sequence of representative cyclic peptides, such as seglitide, tyrothricin, desmethoxymajusculamide C, dudawalamide A, and cyclomarins, in a rapid manner and also were able to provide the first-pass structure evidence of a newly discovered natural product based on predicted sequence. This compound is not available in sufficient quantities for structural elucidation by other means such as NMR. In addition to the development of this cyclic annotation program, it was observed that some cyclic peptides fragmented in unexpected ways resulting in the scrambling of sequences. In summary, MS-CPA not only provides a platform for rapid confirmation and annotation of tandem mass spectrometry data obtained with cyclic peptides but also enables quantitative analysis of the ion intensities. This program facilitates cyclic peptide analysis, sequencing, and also acts as a useful tool to investigate the uncommon fragmentation phenomena of cyclic peptides and aids the characterization of newly discovered cyclic peptides encountered in drug discovery programs.

Dataset Information

Using dissociation energies to predict observability of b- and y-peaks in mass spectra of short peptides.

Publications

Using dissociation energies to predict observability of b- and y-peaks in mass spectra of short peptides.

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