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== Goals == * Predict specificity of peptide recognition domain from the primary amino acid sequence. * Analyze PDZ, WW and then SH3 domains |
== PDZ Domain-Peptide Interaction Prediction == |
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== Strategy == | == Table of Contents == <<TableOfContents>> |
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== Status == * [wiki:/Log Status Log] |
=== Background === The human genome contains approximately 26,000 protein-coding genes, which through alternative splicing can direct the synthesis of thousands of different proteins. The majority of these proteins interact with other proteins to coordinate a variety of cellular processes including DNA replication, cell cycle control, and signal transduction. The ability to accurately detect these interactions enables the assembly of protein interaction networks which can be used to better understand and study the biochemistry of the cell. |
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== Tasks == | === Computational PPI Prediction === Several computational methods to predict protein protein interactions (PPIs) have been developed and can be used to support or prioritize experiments. Such methods fall into a range of categories from physics to statistics-based method, however they all face several challenges. For physics-based prediction methods, the structures of the proteins are often unavailable or protein flexibility is not taken into consideration. Sequence based methods like PWMs can only represent short binding motifs and often do not account for interdependencies between residues and positions. In general, the computational prediction of PPIs is considered an extremely difficult problem that is not fully addressed by any existing method. |
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1. Learn SVN, Brain code (ResidueResidueCorrelation) 1. Literature review related to domain specificity (background activity) 1. Run ResidueResidue correlation analysis on PDZ domain data: 1-1 version + try others e.g. 1-2 (Requires: PDZ profiles from Gary) 1. Implement new feature: amino acid groups (learn amino acid groups) + run on PDZ data 1. Think about new PDZ domain features that can be used for prediction. |
Many PPIs are mediated by peptide recognition domains (PRDs), which are evolutionary conserved modular interaction domains often found combined in different ways to form larger proteins. Proteins containing PRDs are used by the cell for numerous processes such as the co-localization of proteins, regulation of signaling processes or recognition of protein post-translational modifications. Interactions usually occur through the recognition of short linear sequences in the target protein such as proline-rich or C terminal motifs. Because of their simpler binding sites and straightforward modes of target recognition, it is easier to computationally predict peptide-PRD interactions than it is to predict PPIs more generally. |
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== Ideas == * Use of structural data (PDZ domain structures) (may require homology modeling) * Use of machine learning methods (SVM for classification and boosting decision tree for interpretable learning model) * Analysis of correlation within domain and peptide (inter-residue correlation) maybe correspondence analysis |
=== Computational Prediction of PDZ Domain Interactions === The PSD95/DlgA/Zo-1 (PDZ) domain is an ideal model for studying the computational prediction of peptide-PRD interactions since they are have important biological roles, are well studied and one of the simplest binding sites among PRDs. PDZ domains are found in bacteria, yeast, plants, and metazoans with 250 found in humans. They often interact with ion channels, adhesion molecules, and neurotransmitter receptors in signaling and scaffolding proteins. The biological roles include maintaining cell polarity, facilitating signal coupling, and regulating synaptic development. Their importance is emphasized, as mutations of the PDZ domain in different proteins have been associated with various diseases. ==== Sequence Based Prediction ==== Recently, two high through put experiments have been performed to study different PDZ domains. This has enabled the development of computational predictors of PDZ domain interactions. This project focuses on using a machine learning method called support vector machines to computationally predict PDZ domain interactions directly from a given proteome. [[Data/PDZProteomeScanning|[Read More]]] ==== Structure Based Prediction ==== While the previously developed sequence based predictor is able to more accurately and precisely scan proteomes of different organisms for PDZ domain binders, its performance relies on the sequence similarity between testing and training domains. On the other hand, it is known that the domain structure can play a big role in determining PDZ domain binding specificity. Therefore, we developed a structure based predictor of PDZ domain peptide interactions which is trained using PDZ domain structure features. [[Data/StructurePDZProteomeScanning|[Read More]]] ==== POW! PDZ Domain-Peptide Interaction Prediction Website ==== POW is a website that allows users to predict domain-peptide interactions for human, mouse, worm and fly PDZ domains. Predictions are made using a support vector machine (SVM) that was trained using experimentally determined PDZ interaction data from protein microarray and phage display experiments for mouse and human [1,2]. Two types of predictors are available for use. The first is sequence-based (trained using domain and peptide sequence features) while the other structure-based (trained using domain structure and peptide sequence features). POW! Website: http://webservice.baderlab.org/domains/POW/ A simple command line user interface that allows users to run POW! locally on their computer is also available. It is written in Java and can be downloaded below. Please unzip the file below and consult the Readme for more details. POW! CLUI: === Thesis === * [[attachment:Thesis-ShirleyHui-Feb19-2013.pdf|Computational Prediction of PDZ Mediated Protein-Protein Interactions (2013) PDF]] * [[attachment:Thesis-ShirleyHui-Feb19-2013.docx|Computational Prediction of PDZ Mediated Protein-Protein Interactions (2013) WORD]] ## == Goals == ## * Computationally predict specificity of peptide recognition domain from the primary amino acid sequences ## * Analyze PDZ, WW and then SH3 domains ## == Background == ## * [[/PDZ|PDZ Domains]] ## * [[/MachineLearning|Machine Learning]] ## == Strategy == ## * [[/Strategy|Strategy]] ## == Ideas == ## * [[/Ideas|Ideas]] ## == Data == ## * [[/PDZData|PDZ Data]] ## == Experiments == ## * [[/Experiments|Experiments and Results]] ## == Status == ## * [[/Log|Status]] ## == Tasks == ## ## 1. --(Learn SVN, Brain code (!ResidueResidueCorrelation))-- ## 1. Literature review related to domain specificity (background activity), PDZ domains (from Ioana's project) ## 1. --(Run !ResidueResidue correlation analysis on PDZ domain data: 1-1 version + try others e.g. 1-2 (Requires: PDZ profiles from Gary))-- ## 1. MSA subproject ## 1. --(Learn basics of multiple sequence alignment (Baxevanis, chapter 12))-- ## 1. Find and evaluate MSA algorithms (compare notes with Stacy) + evaluate Superfamily, PFAM databases of protein family alignments ## 1. Try different multiple sequence alignment algorithms (MSA) on the PDZ domain sequences to see if they affect the correlation results. ## 1. Benchmark/validate correlation subproject ## 1. We know H (PDZ), T @-2 (peptide) correlation ## 1. Look at structures (e.g. 1N7T and 1BE9) to see if correlated residues/positions are close to each other and compatible (physicochemically). We need to focus on ## PDZ structures that have bound peptides (search in PDB) ## 1. Build set of known true and false correlations for use in evaluating prediction algorithm (Note: also ask Dev Sidhu, when available). See [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10871264 Baldi et al. review] ## 1. Amino acid group subproject ## 1. Learn about amino acid groups ## 1. Define an initial aa grouping (reasonable grouping from Levy paper) ## 1. Add new feature to !ResidueResidueCorrelation class so it considers grouping + run on PDZ data. This involves implementing the groups as a reduced alphabet (amino acids in a group are considered equivalent) ## 1. Try all groupings to see how it affects the results (from Levy paper) ## 1. See if we can incorporate aa similarity defined by substitution matrix approach (e.g. BLOSUM, PAM, GONNET) into our method, instead of grouping ## 1. Similarly, evaluate aa similarity defined by factor analysis (Atchley et al paper) ## 1. Think about new PDZ domain features that can be used for prediction. ## == Ideas == ## * [wiki:/MachineLearning Machine Learning Page] ## * With current correlation counting calculation, Weight calculation by how many peptides are in the peptides file (i.e. normalize the correlation calculation in some way) ## * Build tools to help interpret correlations in the context of multiple sequence alignments (and later structures). ## * Use of structural data (PDZ domain structures) (may require homology modeling) ## * Use of machine learning methods (SVM for classification and boosting decision tree for interpretable learning model) ## * Analysis of correlation within domain and peptide (inter-residue correlation) maybe correspondence analysis ## * Analysis of SNPs and how they affect domain binding (including correlations between SNPs) ## * Define the binding site of the PDZ domain based on phage display data. Given that identical binding sites between two PDZ domains should correspond to identical ## binding specificities, find the set of PDZ domain sites that correlate perfectly with binding specificity. ## == Courses == ## === Biology === ## * [http://bio250y.chass.utoronto.ca/ BIO250] - Cell and Molecular Biology ## * Classes: Tues/Thurs - 1-2 PM (Convocation Hall) OR Mon - 6-8 PM (MC 102-Mechanical Engineering Building) ## * Textbook: [http://www.amazon.com/Molecular-Biology-Fourth-Bruce-Alberts/dp/0815332181/ref=pd_sim_b_1/105-5132391-0345258?ie=UTF8&qid=1188913552&sr=1-4 Molecular Biology of the Cell 4th Ed.] Alberts et al. ## === Protein Structure === ## * BCH340H1 - Proteins: from Structure to Proteomics ## * Classes: Winter 2008 ## * Textbook: ? ## * Previous Course Web Pages: ## * [http://arrhenius.med.utoronto.ca/~chan/bch340h04-outline.html 2004 Chan] ## * [http://xtal.uhnres.utoronto.ca/prive/BCH340/ 2006 Prive] ## === Machine Learning === ## * CSC2515 - Machine Learning ## * Previous Course Web Pages: ## * [http://www.cs.toronto.edu/~roweis/csc2515/ 2003-2006 Roweis] ## == Committee Meetings == ## * [[/Meeting|Notes]] ## == Tools/Resources == ## * [[/ToolsResources|Tools and Resources]] ## == Reading Notes == ## * [[/../ShirleyHui/MBCReadings|Molecular Biology of the Cell]] ## * [[/../ShirleyHui/PPIReadings|Protein-protein Interaction Detection]] ## * Support Vector Machines ## == Related Literature == ## * [[http://www.connotea.org/rss/user/s2hui?download=view|Literature List on Connotea]] ## * [[http://www.baderlab.org/DomainSpecificityPredictionProject/Reading|Molecular Biology of the Cell]] |
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== Documents == == Background Literature == === More General === * The Structure and Function of Proline Recognition Domains, Zarrinpar A, Bhattacharyya RP, Lim WA., Sci STKE. 2003 Apr 22;2003(179):RE8. * attachment:Structure_Function_Pro_Recog_Domains_Zarrinpar_et_al_2003.pdf * Can we infer peptide recognition specificity mediated by SH3 domains?, Cesareni G, Panni S, Nardelli G, Castagnoli L., FEBS Lett. 2002 Feb 20;513(1):38-44. * attachment:Can_we_infer_PR_specificity_med_by_SH3_Cesareni_et_al_2002.pdf * Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits, Bhattacharyya RP, Remenyi A, Yeh BJ, Lim WA., Annu Rev Biochem. 2006;75:655-80. * attachment:Domains_motifs_scaffolds_Bhattacharyya_et_al_2006.pdf === Amino Acid Alphabets === * Simplified amino acid alphabets for protein fold recognition and implications for folding, Murphy LR, Wallqvist A, Levy RM, Protein Eng. 2000 Mar;13(3):149-52. * attachment:Simplified_AA_alphabets_Murphy_2000.pdf * Iterative sequence/secondary structure search for protein homologs: comparison with amino acid sequence alignments and application to fold recognition in genome databases, Wallqvist A, Fukunishi Y, Murphy LR, Fadel A, Levy RM, Bioinformatics. 2000 Nov;16(11):988-1002. * attachment:Iterative_structure_search_for_protein_homologs_Wallqvist_2000.pdf * Simplifying amino acid alphabets by means of a branch and bound algorithm and substitution matrices, Cannata N, Toppo S, Romualdi C, Valle G, Bioinformatics. 2002 Aug;18(8):1102-8. * attachment:Simplifying_AA_alphabets_branch_bound_substit_matrices_Cannata_2002.pdf === PDZ Related === * PDZ domains-glue and guide., van Ham M, Hendriks W., Mol Biol Rep. 2003 Jun;30(2):69-82. * attachment:PDZ_Domains_Glue_and_Guide_2003.pdf * PDZ domains: structural modules for protein complex assembly., Hung AY, Sheng M., J Biol Chem. 2002 Feb 22;277(8):5699-702. Epub 2001 Dec 10. * attachment:PDZ_Domains_Structural_Modules_2001.pdf |
PDZ Domain-Peptide Interaction Prediction
Table of Contents
Contents
Background
The human genome contains approximately 26,000 protein-coding genes, which through alternative splicing can direct the synthesis of thousands of different proteins. The majority of these proteins interact with other proteins to coordinate a variety of cellular processes including DNA replication, cell cycle control, and signal transduction. The ability to accurately detect these interactions enables the assembly of protein interaction networks which can be used to better understand and study the biochemistry of the cell.
Computational PPI Prediction
Several computational methods to predict protein protein interactions (PPIs) have been developed and can be used to support or prioritize experiments. Such methods fall into a range of categories from physics to statistics-based method, however they all face several challenges. For physics-based prediction methods, the structures of the proteins are often unavailable or protein flexibility is not taken into consideration. Sequence based methods like PWMs can only represent short binding motifs and often do not account for interdependencies between residues and positions. In general, the computational prediction of PPIs is considered an extremely difficult problem that is not fully addressed by any existing method.
Many PPIs are mediated by peptide recognition domains (PRDs), which are evolutionary conserved modular interaction domains often found combined in different ways to form larger proteins. Proteins containing PRDs are used by the cell for numerous processes such as the co-localization of proteins, regulation of signaling processes or recognition of protein post-translational modifications. Interactions usually occur through the recognition of short linear sequences in the target protein such as proline-rich or C terminal motifs. Because of their simpler binding sites and straightforward modes of target recognition, it is easier to computationally predict peptide-PRD interactions than it is to predict PPIs more generally.
Computational Prediction of PDZ Domain Interactions
The PSD95/DlgA/Zo-1 (PDZ) domain is an ideal model for studying the computational prediction of peptide-PRD interactions since they are have important biological roles, are well studied and one of the simplest binding sites among PRDs. PDZ domains are found in bacteria, yeast, plants, and metazoans with 250 found in humans. They often interact with ion channels, adhesion molecules, and neurotransmitter receptors in signaling and scaffolding proteins. The biological roles include maintaining cell polarity, facilitating signal coupling, and regulating synaptic development. Their importance is emphasized, as mutations of the PDZ domain in different proteins have been associated with various diseases.
Sequence Based Prediction
Recently, two high through put experiments have been performed to study different PDZ domains. This has enabled the development of computational predictors of PDZ domain interactions. This project focuses on using a machine learning method called support vector machines to computationally predict PDZ domain interactions directly from a given proteome. [Read More]
Structure Based Prediction
While the previously developed sequence based predictor is able to more accurately and precisely scan proteomes of different organisms for PDZ domain binders, its performance relies on the sequence similarity between testing and training domains. On the other hand, it is known that the domain structure can play a big role in determining PDZ domain binding specificity. Therefore, we developed a structure based predictor of PDZ domain peptide interactions which is trained using PDZ domain structure features. [Read More]
POW! PDZ Domain-Peptide Interaction Prediction Website
POW is a website that allows users to predict domain-peptide interactions for human, mouse, worm and fly PDZ domains. Predictions are made using a support vector machine (SVM) that was trained using experimentally determined PDZ interaction data from protein microarray and phage display experiments for mouse and human [1,2]. Two types of predictors are available for use. The first is sequence-based (trained using domain and peptide sequence features) while the other structure-based (trained using domain structure and peptide sequence features).
POW! Website: http://webservice.baderlab.org/domains/POW/
A simple command line user interface that allows users to run POW! locally on their computer is also available. It is written in Java and can be downloaded below. Please unzip the file below and consult the Readme for more details.
POW! CLUI:
Thesis
Computational Prediction of PDZ Mediated Protein-Protein Interactions (2013) PDF
Computational Prediction of PDZ Mediated Protein-Protein Interactions (2013) WORD
Team
- Shirley Hui
- Gary Bader