Dataset Information

Using genome-wide measurements for computational prediction of SH2-peptide interactions.

ABSTRACT: Peptide-recognition modules (PRMs) are used throughout biology to mediate protein-protein interactions, and many PRMs are members of large protein domain families. Recent genome-wide measurements describe networks of peptide-PRM interactions. In these networks, very similar PRMs recognize distinct sets of peptides, raising the question of how peptide-recognition specificity is achieved using similar protein domains. The analysis of individual protein complex structures often gives answers that are not easily applicable to other members of the same PRM family. Bioinformatics-based approaches, one the other hand, may be difficult to interpret physically. Here we integrate structural information with a large, quantitative data set of SH2 domain-peptide interactions to study the physical origin of domain-peptide specificity. We develop an energy model, inspired by protein folding, based on interactions between the amino-acid positions in the domain and peptide. We use this model to successfully predict which SH2 domains and peptides interact and uncover the positions in each that are important for specificity. The energy model is general enough that it can be applied to other members of the SH2 family or to new peptides, and the cross-validation results suggest that these energy calculations will be useful for predicting binding interactions. It can also be adapted to study other PRM families, predict optimal peptides for a given SH2 domain, or study other biological interactions, e.g. protein-DNA interactions.

SUBMITTER: Wunderlich Z

PROVIDER: S-EPMC2724268 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Using genome-wide measurements for computational prediction of SH2-peptide interactions.

Wunderlich Zeba Z Mirny Leonid A LA

Nucleic acids research 20090605 14

Peptide-recognition modules (PRMs) are used throughout biology to mediate protein-protein interactions, and many PRMs are members of large protein domain families. Recent genome-wide measurements describe networks of peptide-PRM interactions. In these networks, very similar PRMs recognize distinct sets of peptides, raising the question of how peptide-recognition specificity is achieved using similar protein domains. The analysis of individual protein complex structures often gives answers that a ...[more]

PMID: 19502496

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Project description:Src homology 2 (SH2) domains are the largest family of the peptide-recognition modules (PRMs) that bind to phosphotyrosine containing peptides. Knowledge about binding partners of SH2-domains is key for a deeper understanding of different cellular processes. Given the high binding specificity of SH2, in-silico ligand peptide prediction is of great interest. Currently however, only a few approaches have been published for the prediction of SH2-peptide interactions. Their main shortcomings range from limited coverage, to restrictive modeling assumptions (they are mainly based on position specific scoring matrices and do not take into consideration complex amino acids inter-dependencies) and high computational complexity. We propose a simple yet effective machine learning approach for a large set of known human SH2 domains. We used comprehensive data from micro-array and peptide-array experiments on 51 human SH2 domains. In order to deal with the high data imbalance problem and the high signal-to-noise ration, we casted the problem in a semi-supervised setting. We report competitive predictive performance w.r.t. state-of-the-art. Specifically we obtain 0.83 AUC ROC and 0.93 AUC PR in comparison to 0.71 AUC ROC and 0.87 AUC PR previously achieved by the position specific scoring matrices (PSSMs) based SMALI approach. Our work provides three main contributions. First, we showed that better models can be obtained when the information on the non-interacting peptides (negative examples) is also used. Second, we improve performance when considering high order correlations between the ligand positions employing regularization techniques to effectively avoid overfitting issues. Third, we developed an approach to tackle the data imbalance problem using a semi-supervised strategy. Finally, we performed a genome-wide prediction of human SH2-peptide binding, uncovering several findings of biological relevance. We make our models and genome-wide predictions, for all the 51 SH2-domains, freely available to the scientific community under the following URLs: http://www.bioinf.uni-freiburg.de/Software/SH2PepInt/SH2PepInt.tar.gz and http://www.bioinf.uni-freiburg.de/Software/SH2PepInt/Genome-wide-predictions.tar.gz, respectively.

Project description:BACKGROUND: Genome-wide identification of specific oligonucleotides (oligos) is a computationally-intensive task and is a requirement for designing microarray probes, primers, and siRNAs. An artificial neural network (ANN) is a machine learning technique that can effectively process complex and high noise data. Here, ANNs are applied to process the unique subsequence distribution for prediction of specific oligos. RESULTS: We present a novel and efficient algorithm, named the integration of ANN and BLAST (IAB) algorithm, to identify specific oligos. We establish the unique marker database for human and rat gene index databases using the hash table algorithm. We then create the input vectors, via the unique marker database, to train and test the ANN. The trained ANN predicted the specific oligos with high efficiency, and these oligos were subsequently verified by BLAST. To improve the prediction performance, the ANN over-fitting issue was avoided by early stopping with the best observed error and a k-fold validation was also applied. The performance of the IAB algorithm was about 5.2, 7.1, and 6.7 times faster than the BLAST search without ANN for experimental results of 70-mer, 50-mer, and 25-mer specific oligos, respectively. In addition, the results of polymerase chain reactions showed that the primers predicted by the IAB algorithm could specifically amplify the corresponding genes. The IAB algorithm has been integrated into a previously published comprehensive web server to support microarray analysis and genome-wide iterative enrichment analysis, through which users can identify a group of desired genes and then discover the specific oligos of these genes. CONCLUSION: The IAB algorithm has been developed to construct SpecificDB, a web server that provides a specific and valid oligo database of the probe, siRNA, and primer design for the human genome. We also demonstrate the ability of the IAB algorithm to predict specific oligos through polymerase chain reaction experiments. SpecificDB provides comprehensive information and a user-friendly interface.

Dataset Information

Using genome-wide measurements for computational prediction of SH2-peptide interactions.

Publications

Using genome-wide measurements for computational prediction of SH2-peptide interactions.

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