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A ranking-based scoring function for peptide-spectrum matches.

ABSTRACT: The analysis of the large volume of tandem mass spectrometry (MS/MS) proteomics data that is generated these days relies on automated algorithms that identify peptides from their mass spectra. An essential component of these algorithms is the scoring function used to evaluate the quality of peptide-spectrum matches (PSMs). In this paper, we present new approach to scoring of PSMs. We argue that since this problem is at its core a ranking task (especially in the case of de novo sequencing), it can be solved effectively using machine learning ranking algorithms. We developed a new discriminative boosting-based approach to scoring. Our scoring models draw upon a large set of diverse feature functions that measure different qualities of PSMs. Our method improves the performance of our de novo sequencing algorithm beyond the current state-of-the-art, and also greatly enhances the performance of database search programs. Furthermore, by increasing the efficiency of tag filtration and improving the sensitivity of PSM scoring, we make it practical to perform large-scale MS/MS analysis, such as proteogenomic search of a six-frame translation of the human genome (in which we achieve a reduction of the running time by a factor of 15 and a 60% increase in the number of identified peptides, compared to the InsPecT database search tool). Our scoring function is incorporated into PepNovo+ which is available for download or can be run online at http://bix.ucsd.edu.

SUBMITTER: Frank AM

PROVIDER: S-EPMC2692183 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

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A ranking-based scoring function for peptide-spectrum matches.

Frank Ari M AM

Journal of proteome research 20090501 5

The analysis of the large volume of tandem mass spectrometry (MS/MS) proteomics data that is generated these days relies on automated algorithms that identify peptides from their mass spectra. An essential component of these algorithms is the scoring function used to evaluate the quality of peptide-spectrum matches (PSMs). In this paper, we present new approach to scoring of PSMs. We argue that since this problem is at its core a ranking task (especially in the case of de novo sequencing), it ca ...[more]

PMID: 19231891

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Project description:BackgroundSmall Proteins have received increasing attention in recent years. They have in particular been implicated as signals contributing to the coordination of bacterial communities. In genome annotations they are often missing or hidden among large numbers of hypothetical proteins because genome annotation pipelines often exclude short open reading frames or over-predict hypothetical proteins based on simple models. The validation of novel proteins, and in particular of small proteins (sProteins), therefore requires additional evidence. Proteogenomics is considered the gold standard for this purpose. It extends beyond established annotations and includes all possible open reading frames (ORFs) as potential sources of peptides, thus allowing the discovery of novel, unannotated proteins. Typically this results in large numbers of putative novel small proteins fraught with large fractions of false-positive predictions.ResultsWe observe that number and quality of the peptide-spectrum matches (PSMs) that map to a candidate ORF can be highly informative for the purpose of distinguishing proteins from spurious ORF annotations. We report here on a workflow that aggregates PSM quality information and local context into simple descriptors and reliably separates likely proteins from the large pool of false-positive, i.e., most likely untranslated ORFs. We investigated the artificial gut microbiome model SIHUMIx, comprising eight different species, for which we validate 5114 proteins that have previously been annotated only as hypothetical ORFs. In addition, we identified 37 non-annotated protein candidates for which we found evidence at the proteomic and transcriptomic level. Half (19) of these candidates have close functional homologs in other species. Another 12 candidates have homologs designated as hypothetical proteins in other species. The remaining six candidates are short (< 100 AA) and are most likely bona fide novel proteins.ConclusionsThe aggregation of PSM quality information for predicted ORFs provides a robust and efficient method to identify novel proteins in proteomics data. The workflow is in particular capable of identifying small proteins and frameshift variants. Since PSMs are explicitly mapped to genomic locations, it furthermore facilitates the integration of transcriptomics data and other sources of genome-level information.

Project description:Molecular-docking programs coupled with suitable scoring functions are now established and very useful tools enabling computational chemists to rapidly screen large chemical databases and thereby to identify promising candidate compounds for further experimental processing. In a broader scenario, predicting binding affinity is one of the most critical and challenging components of computer-aided structure-based drug design. The development of a molecular docking scoring function which in principle could combine both features, namely ranking putative poses and predicting complex affinity, would be of paramount importance. Here, we systematically investigated the performance of the MM-PBSA approach, using two different Poisson-Boltzmann solvers (APBS and DelPhi), in the currently rising field of protein-peptide interactions (PPIs), identifying the correct binding conformations of 19 different protein-peptide complexes and predicting their binding free energies. First, we scored the decoy structures from HADDOCK calculation via the MM-PBSA approach in order to assess the capability of retrieving near-native poses in the best-scoring clusters and of evaluating the corresponding free energies of binding. MM-PBSA behaves well in finding the poses corresponding to the lowest binding free energy, however the built-in HADDOCK score shows a better performance. In order to improve the MM-PBSA-based scoring function, we dampened the MM-PBSA solvation and coulombic terms by 0.2, as proposed in the HADDOCK score and LIE approaches. The new dampened MM-PBSA (dMM-PBSA) outperforms the original MM-PBSA and ranks the decoys structures as the HADDOCK score does. Second, we found a good correlation between the dMM-PBSA and HADDOCK scores for the near-native clusters of each system and the experimental binding energies, respectively. Therefore, we propose a new scoring function, dMM-PBSA, to be used together with the built-in HADDOCK score in the context of protein-peptide docking simulations.

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A ranking-based scoring function for peptide-spectrum matches.

Publications

A ranking-based scoring function for peptide-spectrum matches.

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