OntoPIN: An ontology-annotated PPI database

Protein-protein interaction (PPI) data are often stored in publicly available databases that are often queried by the use of simple query interfaces allowing only key-based queries. Such databases enable the retrieval of one or more proteins that interact with a target protein, using a target protein identifier. Nevertheless, a lot of biological information is available and is spread on different sources and encoded in different ontologies (e.g. Gene Ontology). Annotating existing PPI databases with biological information may result in richer querying interfaces and successively could enable the development of novel algorithms that may use biological information. The OntoPIN project showed the effectiveness of the introduction of a framework for the ontology-based management and querying of Protein-Protein Interaction Data. The OntoPIN framework first merges PPI data with annotations extracted from existing ontologies (e.g. Gene Ontology) and stores annotated data into a database. Then, a semantic-based query interface enables users to query these data by using biological concepts. OntoPIN allows: (a) to extend existing PPI databases by using ontologies, (b) to enable a key-based querying of annotated data, and (c) to offer a novel query interface based on semantic similarity among annotations. This paper presents the current state of the OntoPIN project discussing a case study on human protein interaction data.

Structural genomics provides an important approach for characterizing and understanding systems biology. As a step toward better integrating protein three-dimensional (3D) structural information in cancer systems biology, we have constructed a Human Cancer Pathway Protein Interaction Network (HCPIN) by analysis of several classical cancer-associated signaling pathways and their physical protein-protein interactions. Many well known cancer-associated proteins play central roles as "hubs" or "bottlenecks" in the HCPIN. At least half of HCPIN proteins are either directly associated with or interact with multiple signaling pathways. Although some 45% of residues in these proteins are in sequence segments that meet criteria sufficient for approximate homology modeling (Basic Local Alignment Search Tool (BLAST) E-value <10(-6)), only approximately 20% of residues in these proteins are structurally covered using high accuracy homology modeling criteria (i.e. BLAST E-value <10(-6) and at least 80% sequence identity) or by actual experimental structures. The HCPIN Website provides a comprehensive description of this biomedically important multipathway network together with experimental and homology models of HCPIN proteins useful for cancer biology research. To complement and enrich cancer systems biology, the Northeast Structural Genomics Consortium is targeting >1000 human proteins and protein domains from the HCPIN for sample production and 3D structure determination. The long range goal of this effort is to provide a comprehensive 3D structure-function database for human cancer-associated proteins and protein complexes in the context of their interaction networks. The network-based target selection (BioNet) approach described here is an example of a general strategy for targeting co-functioning proteins by structural genomics projects.

Signal flow direction is one of the most important features of the protein-protein interactions in signaling networks. However, almost all the outcomes of current high-throughout techniques for protein-protein interactions mapping are usually supposed to be non-directional. Based on the pairwise interaction domains, here we defined a novel parameter protein interaction directional score and then used it to predict the direction of signal flow between proteins in proteome-wide signaling networks. Using 5-fold cross-validation, our approach obtained a satisfied performance with the accuracy 89.79%, coverage 48.08%, and error ratio 16.91%. As an application, we established an integrated human directional protein interaction network, including 2,237 proteins and 5,530 interactions, and inferred a large amount of novel signaling pathways. Directional protein interaction network was strongly supported by the known signaling pathways literature (with the 87.5% accuracy) and further analyses on the biological annotation, subcellular localization, and network topology property. Thus, this study provided an effective method to define the upstream/downstream relations of interacting protein pairs and a powerful tool to unravel the unknown signaling pathways.

Protein complexes are a cornerstone of many biological processes. Protein-protein interaction (PPI) data enable a number of computational methods for predicting protein complexes. However, the insufficiency of the PPI data significantly lowers the accuracy of computational methods. In the current work, the authors develop a novel method named clustering based on multiple biological information (CMBI) to discover protein complexes via the integration of multiple biological resources including gene expression profiles, essential protein information and PPI data. First, CMBI defines the functional similarity of each pair of interacting proteins based on the edge-clustering coefficient and the Pearson correlation coefficient. Second, CMBI selects essential proteins as seeds to build the protein complexes. A redundancy-filtering procedure is performed to eliminate redundant complexes. In addition to the essential proteins, CMBI also uses other proteins as seeds to expand protein complexes. To check the performance of CMBI, the authors compare the complexes discovered by CMBI with the ones found by other techniques by matching the predicted complexes against the reference complexes. The authors use subsequently GO::TermFinder to analyse the complexes predicted by various methods. Finally, the effect of parameters T and R is investigated. The results from GO functional enrichment and matching analyses show that CMBI performs significantly better than the state-of-the-art methods.

The exploding number of computational models produced by Systems Biologists over the last years is an invitation to structure and exploit this new wealth of information. Researchers would like to trace models relevant to specific scientific questions, to explore their biological content, to align and combine them, and to match them with experimental data. To automate these processes, it is essential to consider semantic annotations, which describe their biological meaning. As a prerequisite for a wide range of computational methods, we propose general and flexible similarity measures for Systems Biology models computed from semantic annotations. By using these measures and a large extensible ontology, we implement a platform that can retrieve, cluster, and align Systems Biology models and experimental data sets. At present, its major application is the search for relevant models in the BioModels Database, starting from initial models, data sets, or lists of biological concepts. Beyond similarity searches, the representation of models by semantic feature vectors may pave the way for visualisation, exploration, and statistical analysis of large collections of models and corresponding data.

Protein-protein interaction (PPI) data is essential to elucidate the complex molecular relationships in living systems, and thus understand the biological functions at cellular and systems levels. The complete map of PPIs that can occur in a living organism is called the interactome. For animals, PPI data is stored in multiple databases (e.g., BioGRID, CCSB, DroID, FlyBase, HIPPIE, HitPredict, HomoMINT, INstruct, Interactome3D, mentha, MINT, and PINA2) with different formats. This makes PPI comparisons difficult to perform, especially between species, since orthologous proteins may have different names. Moreover, there is only a partial overlap between databases, even when considering a single species. The EvoPPI ( http://evoppi.i3s.up.pt ) web application presented in this paper allows comparison of data from the different databases at the species level, or between species using a BLAST approach. We show its usefulness by performing a comparative study of the interactome of the nine polyglutamine (polyQ) disease proteins, namely androgen receptor (AR), atrophin-1 (ATN1), ataxin 1 (ATXN1), ataxin 2 (ATXN2), ataxin 3 (ATXN3), ataxin 7 (ATXN7), calcium voltage-gated channel subunit alpha1 A (CACNA1A), Huntingtin (HTT), and TATA-binding protein (TBP). Here we show that none of the human interactors of these proteins is common to all nine interactomes. Only 15 proteins are common to at least 4 of these polyQ disease proteins, and 40% of these are involved in ubiquitin protein ligase-binding function. The results obtained in this study suggest that polyQ disease proteins are involved in different functional networks. Comparisons with Mus musculus PPIs are also made for AR and TBP, using EvoPPI BLAST search approach (a unique feature of EvoPPI), with the goal of understanding why there is a significant excess of common interactors for these proteins in humans.

In biomedical applications, network models are commonly used to represent interactions and higher-level associations among biological entities. Integrated analyses of these interaction and association data has proven useful in extracting knowledge, and generating novel hypotheses for biomedical research. For example, integrated mining of clinical similarity among diseases, known disease-gene associations, and molecular interactions among proteins provide insight on prioritizing candidate disease genes. However, since most datasets provide their own schema and query interface, opportunities for exploratory and integrative querying of disparate data are currently limited. In this study, we capitalize on RDF-based representations of biomedical interaction and association data to develop a querying framework that enables efficient processing and flexible specification of graph template matching queries. The proposed framework enables integrative querying of biomedical databases to discover complex patterns of associations among a diverse range of biological entities, including biomolecules, biological processes, organisms, and phenotypes. Our experimental results on the UniProt dataset show the proposed framework can be used to efficiently process complex queries, and identify biologically relevant patterns of associations that cannot be readily obtained by querying each dataset independently.

Evolutionary algorithms (EAs), as global search methods, are proved to be more robust than their counterpart local heuristics for detecting protein complexes in protein-protein interaction (PPI) networks. Typically, the source of robustness of these EAs comes from their components and parameters. These components are solution representation, selection, crossover, and mutation. Unfortunately, almost all EA based complex detection methods suggested in the literature were designed with only canonical or traditional components. Further, topological structure of the protein network is the main information that is used in the design of almost all such components. The main contribution of this paper is to formulate a more robust EA with more biological consistency. For this purpose, a new crossover operator is suggested where biological information in terms of both gene semantic similarity and protein functional similarity is fed into its design. To reflect the heuristic roles of both semantic and functional similarities, this paper introduces two gene ontology (GO) aware crossover operators. These are direct annotation-aware and inherited annotation-aware crossover operators. The first strategy is handled with the direct gene ontology annotation of the proteins, while the second strategy is handled with the directed acyclic graph (DAG) of each gene ontology term in the gene product. To conduct our experiments, the proposed EAs with GO-aware crossover operators are compared against the state-of-the-art heuristic, canonical EAs with the traditional crossover operator, and GO-based EAs. Simulation results are evaluated in terms of recall, precision, and F measure at both complex level and protein level. The results prove that the new EA design encourages a more reliable treatment of exploration and exploitation and, thus, improves the detection ability for more accurate protein complex structures.

BackgroundMolecular interaction data at proteomic and genetic levels provide physical and functional insights into a molecular biosystem and are helpful for the construction of pathway structures complementarily. Despite advances in inferring biological pathways using genetic interaction data, there still exists weakness in developed models, such as, activity pathway networks (APN), when integrating the data from proteomic and genetic levels. It is necessary to develop new methods to infer pathway structure by both of interaction data.ResultsWe utilized probabilistic graphical model to develop a new method that integrates genetic interaction and protein interaction data and infers exquisitely detailed pathway structure. We modeled the pathway network as Bayesian network and applied this model to infer pathways for the coherent subsets of the global genetic interaction profiles, and the available data set of endoplasmic reticulum genes. The protein interaction data were derived from the BioGRID database. Our method can accurately reconstruct known cellular pathway structures, including SWR complex, ER-Associated Degradation (ERAD) pathway, N-Glycan biosynthesis pathway, Elongator complex, Retromer complex, and Urmylation pathway. By comparing N-Glycan biosynthesis pathway and Urmylation pathway identified from our approach with that from APN, we found that our method is able to overcome its weakness (certain edges are inexplicable). According to underlying protein interaction network, we defined a simple scoring function that only adopts genetic interaction information to avoid the balance difficulty in the APN. Using the effective stochastic simulation algorithm, the performance of our proposed method is significantly high.ConclusionWe developed a new method based on Bayesian network to infer detailed pathway structures from interaction data at proteomic and genetic levels. The results indicate that the developed method performs better in predicting signaling pathways than previously described models.

BackgroundProtein-protein interactions are at the basis of most cellular processes and crucial for many bio-technological applications. During the last few years the development of high-throughput technologies has produced several large-scale protein-protein interaction data sets for various organisms. It is important to develop tools for dissecting their content and analyse the information they embed by data-integration and computational methods.ResultsInteractions can be mediated by the presence of specific features, such as motifs, surface patches and domains. The co-occurrence of these features on proteins interacting with the same protein can indicate mutually exclusive interactions and, therefore, can be used for inferring the involvement of the proteins in common biological processes.We present here a publicly available server that allows the user to investigate protein interaction data in light of other biological information, such as their sequences, presence of specific domains, process and component ontologies. The server can be effectively used to construct a high-confidence set of mutually exclusive interactions by identifying similar features in groups of proteins sharing a common interaction partner. As an example, we describe here the identification of common motifs, function, cellular localization and domains in different datasets of yeast interactions.ConclusionsThe server can be used to analyse user-supplied datasets, it contains pre-processed data for four yeast Protein Protein interaction datasets and the results of their statistical analysis. These show that the presence of common motifs in proteins interacting with the same partner is a valuable source of information, it can be used to investigate the properties of the interacting proteins and provides information that can be effectively integrated with other sources. As more experimental interaction data become available, this tool will become more and more useful to gain a more detailed picture of the interactome.

BackgroundEssential proteins are distinctly important for an organism’s survival and development and crucial to disease analysis and drug design as well. Large-scale protein-protein interaction (PPI) data sets exist in Saccharomyces cerevisiae, which provides us with a valuable opportunity to predict identify essential proteins from PPI networks. Many network topology-based computational methods have been designed to detect essential proteins. However, these methods are limited by the completeness of available PPI data. To break out of these restraints, some computational methods have been proposed by integrating PPI networks and multi-source biological data. Despite the progress in the research of multiple data fusion, it is still challenging to improve the prediction accuracy of the computational methods.ResultsIn this paper, we design a novel iterative model for essential proteins prediction, named Randomly Walking in the Heterogeneous Network (RWHN). In RWHN, a weighted protein-protein interaction network and a domain-domain association network are constructed according to the original PPI network and the known protein-domain association network, firstly. And then, we establish a new heterogeneous matrix by combining the two constructed networks with the protein-domain association network. Based on the heterogeneous matrix, a transition probability matrix is established by normalized operation. Finally, an improved PageRank algorithm is adopted on the heterogeneous network for essential proteins prediction. In order to eliminate the influence of the false negative, information on orthologous proteins and the subcellular localization information of proteins are integrated to initialize the score vector of proteins. In RWHN, the topology, conservative and functional features of essential proteins are all taken into account in the prediction process. The experimental results show that RWHN obviously exceeds in predicting essential proteins ten other competing methods.ConclusionsWe demonstrated that integrating multi-source data into a heterogeneous network can preserve the complex relationship among multiple biological data and improve the prediction accuracy of essential proteins. RWHN, our proposed method, is effective for the prediction of essential proteins.

Motivations. Available biomolecular annotations are very valuable, but dispersed and far from being complete. High quality integration of scattered annotation data and reliable identification of new annotations can greatly support unveiling new biomedical knowledge. Biomolecular interactions are one of the main objectives of biomolecular studies, due to the understanding that biological processes are mainly driven by interactions among biomolecular entities, such as proteins and DNA. New powerful high-throughput experimental techniques are providing numerous protein-protein interaction data; they are being collected, together with computational results, in several different databases, which include IntAct, BioGrid, BIND, DIP, HPRD and MINT. Yet, they generally do not include phenotypic or even functional or structural information about the interactors, which in many cases are available in other databases. In particular, no information is available about the association of protein-protein interactions with genetic disorders. This creates the need to integrate the sparsely available data in order to enrich the identified interactions with additional evidence, support their biological interpretation and identify their involvement in inherited pathologies. In addition, integration of gene and protein annotations and protein-protein interaction data provides the base to infer new gene annotations and interaction networks. Methods. We developed an automatic association inference method, based on the transitive closure concept, and applied it on the data from several distributed sources integrated in our Genomic and Proteomic Data Warehouse (GPDW). In particular, by leveraging protein-protein interaction data, provided by the IntAct and MINT databases, and protein encoding gene data form the Entrez Gene database, we inferred gene interaction networks. In addition, by taking advantage of genetic disorder and phenotype data provided by the OMIM database, we inferred associations between proteins and genetic disorders and their phenotypes. Then, in order to identify genetic disorders possibly associated with protein-protein interactions, we looked for those interacting proteins that resulted associated with the same genetic disorder. Results. Our GPDW currently includes 46,154 human protein-protein interactions (out of the 254,048 protein-protein interactions contained), which involve 12,178 different human proteins (out of the 326,766 human proteins in the GPDW) that are encoded by 11,232 different human genes. By applying the above described method, we identified 1,130 gene networks and found 1,136 human protein-protein interactions associated with 628 genetic disorders (6% of all genetic disorders in the GPDW), which are related to 86 clinical synopses (87% of all clinical synopses in the GPDW) and 3,481 phenotypes (10% of the total phenotypes in the GPDW). Among others, we found four interacting proteins (AHSA1_HUMAN, CFTR_HUMAN, DERL1_HUMAN, and RNF5_HUMAN) whose encoding genes are known to be associated with cystic fibrosis, as well as other 43 genes. Mutations of the CFTR human gene are known to be directly involved in different grades and manifestations of cystic fibrosis. The found associations of the AHSA1_HUMAN, CFTR_HUMAN, DERL1_HUMAN, and RNF5_HUMAN interacting proteins with cystic fibrosis could suggest that some types of this multi-variant disorder may be associated with defects in the interactions between these proteins. Possibly, different CFTR_HUMAN protein mutations could alter its functional interaction with one or more of the AHSA1_HUMAN, DERL1_HUMAN and RNF5_HUMAN proteins. If this would be proven, such finding would also suggest, as a possible disease treatment strategy, the engineering of a synthetic protein interacting with the mutated CFTR_HUMAN protein and similar in function to the one of the AHSA1_HUMAN, DERL1_HUMAN or RNF5_HUMAN proteins whose interactions with the mutated CFTR_HUMAN protein result altered. The above discussed findings demonstrate the importance of the transitive closure based inference method developed, as well as of the data integration approach implemented in the GPDW and the relevance of the comprehensive data there integrated. Availability The GPDW constitutes the backend of a Genomic and Proteomic Knowledge Base (GPKB) that is publicly available at http://www.bioinformatics.dei.polimi.it/GPKB/ through a prototype easy-to-use and efficient Web interface.

BackgroundProtein-protein interaction (PPI) data are widely used to generate network models that aim to describe the relationships between proteins in biological systems. The fidelity and completeness of such networks is primarily limited by the paucity of protein interaction information and by the restriction of most of these data to just a few widely studied experimental organisms. In order to extend the utility of existing PPIs, computational methods can be used that exploit functional conservation between orthologous proteins across taxa to predict putative PPIs or 'interologs'. To date most interolog prediction efforts have been restricted to specific biological domains with fixed underlying data sources and there are no software tools available that provide a generalised framework for 'on-the-fly' interolog prediction.ResultsWe introduce Bio::Homology::InterologWalk, a Perl module to retrieve, prioritise and visualise putative protein-protein interactions through an orthology-walk method. The module uses orthology and experimental interaction data to generate putative PPIs and optionally collates meta-data into an Interaction Prioritisation Index that can be used to help prioritise interologs for further analysis. We show the application of our interolog prediction method to the genomic interactome of the fruit fly, Drosophila melanogaster. We analyse the resulting interaction networks and show that the method proposes new interactome members and interactions that are candidates for future experimental investigation.ConclusionsOur interolog prediction tool employs the Ensembl Perl API and PSICQUIC enabled protein interaction data sources to generate up to date interologs 'on-the-fly'. This represents a significant advance on previous methods for interolog prediction as it allows the use of the latest orthology and protein interaction data for all of the genomes in Ensembl. The module outputs simple text files, making it easy to customise the results by post-processing, allowing the putative PPI datasets to be easily integrated into existing analysis workflows. The Bio::Homology::InterologWalk module, sample scripts and full documentation are freely available from the Comprehensive Perl Archive Network (CPAN) under the GNU Public license.

BackgroundVisualization concerns the representation of data visually and is an important task in scientific research. Protein-protein interactions (PPI) are discovered using either wet lab techniques, such mass spectrometry, or in silico predictions tools, resulting in large collections of interactions stored in specialized databases. The set of all interactions of an organism forms a protein-protein interaction network (PIN) and is an important tool for studying the behaviour of the cell machinery. Since graphic representation of PINs may highlight important substructures, e.g. protein complexes, visualization is more and more used to study the underlying graph structure of PINs. Although graphs are well known data structures, there are different open problems regarding PINs visualization: the high number of nodes and connections, the heterogeneity of nodes (proteins) and edges (interactions), the possibility to annotate proteins and interactions with biological information extracted by ontologies (e.g. Gene Ontology) that enriches the PINs with semantic information, but complicates their visualization.MethodsIn these last years many software tools for the visualization of PINs have been developed. Initially thought for visualization only, some of them have been successively enriched with new functions for PPI data management and PIN analysis. The paper analyzes the main software tools for PINs visualization considering four main criteria: (i) technology, i.e. availability/license of the software and supported OS (Operating System) platforms; (ii) interoperability, i.e. ability to import/export networks in various formats, ability to export data in a graphic format, extensibility of the system, e.g. through plug-ins; (iii) visualization, i.e. supported layout and rendering algorithms and availability of parallel implementation; (iv) analysis, i.e. availability of network analysis functions, such as clustering or mining of the graph, and the possibility to interact with external databases.ResultsCurrently, many tools are available and it is not easy for the users choosing one of them. Some tools offer sophisticated 2D and 3D network visualization making available many layout algorithms, others tools are more data-oriented and support integration of interaction data coming from different sources and data annotation. Finally, some specialistic tools are dedicated to the analysis of pathways and cellular processes and are oriented toward systems biology studies, where the dynamic aspects of the processes being studied are central.ConclusionA current trend is the deployment of open, extensible visualization tools (e.g. Cytoscape), that may be incrementally enriched by the interactomics community with novel and more powerful functions for PIN analysis, through the development of plug-ins. On the other hand, another emerging trend regards the efficient and parallel implementation of the visualization engine that may provide high interactivity and near real-time response time, as in NAViGaTOR. From a technological point of view, open-source, free and extensible tools, like Cytoscape, guarantee a long term sustainability due to the largeness of the developers and users communities, and provide a great flexibility since new functions are continuously added by the developer community through new plug-ins, but the emerging parallel, often closed-source tools like NAViGaTOR, can offer near real-time response time also in the analysis of very huge PINs.

HCVpro: Hepatitis C virus protein interaction database