Effect of reference genome selection on the performance of computational methods for genome-wide protein-protein interaction prediction

Background

Recent progress in computational methods for predicting physical and functional protein-protein interactions has provided new insights into the complexity of biological processes. Most of these methods assume that functionally interacting proteins are likely to have a shared evolutionary history. This history can be traced out for the protein pairs of a query genome by correlating different evolutionary aspects of their homologs in multiple genomes known as the reference genomes. These methods include phylogenetic profiling, gene neighborhood and co-occurrence of the orthologous protein coding genes in the same cluster or operon. These are collectively known as genomic context methods. On the other hand a method called mirrortree is based on the similarity of phylogenetic trees between two interacting proteins. Comprehensive performance analyses of these methods have been frequently reported in literature. However, very few studies provide insight into the effect of reference genome selection on detection of meaningful protein interactions.

Methods

We analyzed the performance of four methods and their variants to understand the effect of reference genome selection on prediction efficacy. We used six sets of reference genomes, sampled in accordance with phylogenetic diversity and relationship between organisms from 565 bacteria. We used Escherichia coli as a model organism and the gold standard datasets of interacting proteins reported in DIP, EcoCyc and KEGG databases to compare the performance of the prediction methods.

Conclusions

Higher performance for predicting protein-protein interactions was achievable even with 100–150 bacterial genomes out of 565 genomes. Inclusion of archaeal genomes in the reference genome set improves performance. We find that in order to obtain a good performance, it is better to sample few genomes of related genera of prokaryotes from the large number of available genomes. Moreover, such a sampling allows for selecting 50–100 genomes for comparable accuracy of predictions when computational resources are limited.     

A protein domain interaction interface database: InterPare

Background  

Most proteins function by interacting with other molecules. Their interaction interfaces are highly conserved throughout evolution to avoid undesirable interactions that lead to fatal disorders in cells. Rational drug discovery includes computational methods to identify the interaction sites of lead compounds to the target molecules. Identifying and classifying protein interaction interfaces on a large scale can help researchers discover drug targets more efficiently.     

Predicting protein-protein interactions in unbalanced data using the primary structure of proteins

Background  

Elucidating protein-protein interactions (PPIs) is essential to constructing protein interaction networks and facilitating our understanding of the general principles of biological systems. Previous studies have revealed that interacting protein pairs can be predicted by their primary structure. Most of these approaches have achieved satisfactory performance on datasets comprising equal number of interacting and non-interacting protein pairs. However, this ratio is highly unbalanced in nature, and these techniques have not been comprehensively evaluated with respect to the effect of the large number of non-interacting pairs in realistic datasets. Moreover, since highly unbalanced distributions usually lead to large datasets, more efficient predictors are desired when handling such challenging tasks.     

Exploiting Amino Acid Composition for Predicting Protein-Protein Interactions

Background

Computational prediction of protein interactions typically use protein domains as classifier features because they capture conserved information of interaction surfaces. However, approaches relying on domains as features cannot be applied to proteins without any domain information. In this paper, we explore the contribution of pure amino acid composition (AAC) for protein interaction prediction. This simple feature, which is based on normalized counts of single or pairs of amino acids, is applicable to proteins from any sequenced organism and can be used to compensate for the lack of domain information.

Results

AAC performed at par with protein interaction prediction based on domains on three yeast protein interaction datasets. Similar behavior was obtained using different classifiers, indicating that our results are a function of features and not of classifiers. In addition to yeast datasets, AAC performed comparably on worm and fly datasets. Prediction of interactions for the entire yeast proteome identified a large number of novel interactions, the majority of which co-localized or participated in the same processes. Our high confidence interaction network included both well-studied and uncharacterized proteins. Proteins with known function were involved in actin assembly and cell budding. Uncharacterized proteins interacted with proteins involved in reproduction and cell budding, thus providing putative biological roles for the uncharacterized proteins.

Conclusion

AAC is a simple, yet powerful feature for predicting protein interactions, and can be used alone or in conjunction with protein domains to predict new and validate existing interactions. More importantly, AAC alone performs at par with existing, but more complex, features indicating the presence of sequence-level information that is predictive of interaction, but which is not necessarily restricted to domains.     

Predicting co-complexed protein pairs using genomic and proteomic data integration

Background  

Identifying all protein-protein interactions in an organism is a major objective of proteomics. A related goal is to know which protein pairs are present in the same protein complex. High-throughput methods such as yeast two-hybrid (Y2H) and affinity purification coupled with mass spectrometry (APMS) have been used to detect interacting proteins on a genomic scale. However, both Y2H and APMS methods have substantial false-positive rates. Aside from high-throughput interaction screens, other gene- or protein-pair characteristics may also be informative of physical interaction. Therefore it is desirable to integrate multiple datasets and utilize their different predictive value for more accurate prediction of co-complexed relationship.     

Estimation and efficient computation of the true probability of recurrence of short linear protein sequence motifs in unrelated proteins

Background  

Large datasets of protein interactions provide a rich resource for the discovery of Short Linear Motifs (SLiMs) that recur in unrelated proteins. However, existing methods for estimating the probability of motif recurrence may be biased by the size and composition of the search dataset, such that p-value estimates from different datasets, or from motifs containing different numbers of non-wildcard positions, are not strictly comparable. Here, we develop more exact methods and explore the potential biases of computationally efficient approximations.     

Phylogenetic tree information aids supervised learning for predicting protein-protein interaction based on distance matrices

Background  

Protein-protein interactions are critical for cellular functions. Recently developed computational approaches for predicting protein-protein interactions utilize co-evolutionary information of the interacting partners, e.g., correlations between distance matrices, where each matrix stores the pairwise distances between a protein and its orthologs from a group of reference genomes.     

Quantitative analysis of EGR proteins binding to DNA: assessing additivity in both the binding site and the protein

Background  

Recognition codes for protein-DNA interactions typically assume that the interacting positions contribute additively to the binding energy. While this is known to not be precisely true, an additive model over the DNA positions can be a good approximation, at least for some proteins. Much less information is available about whether the protein positions contribute additively to the interaction.     

SpectralNET – an application for spectral graph analysis and visualization

Background  

Graph theory provides a computational framework for modeling a variety of datasets including those emerging from genomics, proteomics, and chemical genetics. Networks of genes, proteins, small molecules, or other objects of study can be represented as graphs of nodes (vertices) and interactions (edges) that can carry different weights. SpectralNET is a flexible application for analyzing and visualizing these biological and chemical networks.     

Prediction of GTP interacting residues,dipeptides and tripeptides in a protein from its evolutionary information

Background  

Guanosine triphosphate (GTP)-binding proteins play an important role in regulation of G-protein. Thus prediction of GTP interacting residues in a protein is one of the major challenges in the field of the computational biology. In this study, an attempt has been made to develop a computational method for predicting GTP interacting residues in a protein with high accuracy (Acc), precision (Prec) and recall (Rc).     

Computational verification of protein-protein interactions by orthologous co-expression

Background  

High-throughput methods identify an overwhelming number of protein-protein interactions. However, the limited accuracy of these methods results in the false identification of many spurious interactions. Accordingly, the resulting interactions are regarded as hypothetical and computational methods are needed to increase their confidence. Several methods have recently been suggested for this purpose including co-expression as a confidence measure for interacting proteins, but their performance is still quite poor.     

Gene identification and protein classification in microbial metagenomic sequence data via incremental clustering

Background  

The identification and study of proteins from metagenomic datasets can shed light on the roles and interactions of the source organisms in their communities. However, metagenomic datasets are characterized by the presence of organisms with varying GC composition, codon usage biases etc., and consequently gene identification is challenging. The vast amount of sequence data also requires faster protein family classification tools.     

Exploiting structural and topological information to improve prediction of RNA-protein binding sites

Background  

RNA-protein interactions are important for a wide range of biological processes. Current computational methods to predict interacting residues in RNA-protein interfaces predominately rely on sequence data. It is, however, known that interface residue propensity is closely correlated with structural properties. In this paper we systematically study information obtained from sequences and structures and compare their contributions in this prediction problem. Particularly, different geometrical and network topological properties of protein structures are evaluated to improve interface residue prediction accuracy.     

A New Method for the Discovery of Essential Proteins

Background

Experimental methods for the identification of essential proteins are always costly, time-consuming, and laborious. It is a challenging task to find protein essentiality only through experiments. With the development of high throughput technologies, a vast amount of protein-protein interactions are available, which enable the identification of essential proteins from the network level. Many computational methods for such task have been proposed based on the topological properties of protein-protein interaction (PPI) networks. However, the currently available PPI networks for each species are not complete, i.e. false negatives, and very noisy, i.e. high false positives, network topology-based centrality measures are often very sensitive to such noise. Therefore, exploring robust methods for identifying essential proteins would be of great value.

Method

In this paper, a new essential protein discovery method, named CoEWC (Co-Expression Weighted by Clustering coefficient), has been proposed. CoEWC is based on the integration of the topological properties of PPI network and the co-expression of interacting proteins. The aim of CoEWC is to capture the common features of essential proteins in both date hubs and party hubs. The performance of CoEWC is validated based on the PPI network of Saccharomyces cerevisiae. Experimental results show that CoEWC significantly outperforms the classical centrality measures, and that it also outperforms PeC, a newly proposed essential protein discovery method which outperforms 15 other centrality measures on the PPI network of Saccharomyces cerevisiae. Especially, when predicting no more than 500 proteins, even more than 50% improvements are obtained by CoEWC over degree centrality (DC), a better centrality measure for identifying protein essentiality.

Conclusions

We demonstrate that more robust essential protein discovery method can be developed by integrating the topological properties of PPI network and the co-expression of interacting proteins. The proposed centrality measure, CoEWC, is effective for the discovery of essential proteins.     

Open source tool for prediction of genome wide protein-protein interaction network based on ortholog information

Background  

Protein-protein interactions are crucially important for cellular processes. Knowledge of these interactions improves the understanding of cell cycle, metabolism, signaling, transport, and secretion. Information about interactions can hint at molecular causes of diseases, and can provide clues for new therapeutic approaches. Several (usually expensive and time consuming) experimental methods can probe protein - protein interactions. Data sets, derived from such experiments make the development of prediction methods feasible, and make the creation of protein-protein interaction network predicting tools possible.     

A database and tool, IM Browser, for exploring and integrating emerging gene and protein interaction data forDrosophila

Background  

Biological processes are mediated by networks of interacting genes and proteins. Efforts to map and understand these networks are resulting in the proliferation of interaction data derived from both experimental and computational techniques for a number of organisms. The volume of this data combined with the variety of specific forms it can take has created a need for comprehensive databases that include all of the available data sets, and for exploration tools to facilitate data integration and analysis. One powerful paradigm for the navigation and analysis of interaction data is an interaction graph or map that represents proteins or genes as nodes linked by interactions. Several programs have been developed for graphical representation and analysis of interaction data, yet there remains a need for alternative programs that can provide casual users with rapid easy access to many existing and emerging data sets.     

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

Background

Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials.

Methodology/Principal Findings

To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins.

Conclusions/Significance

Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents.     

GANDivAWeb: A web server for detecting early folding units ("foldons") from protein 3D structures

Background  

It has long been known that small regions of proteins tend to fold independently and are then stabilized by interactions between these distinct subunits or modules. Such units, also known as autonomous folding units (AFUs) or"foldons" play a key role in protein folding. A knowledge of such early folding units has diverse applications in protein engineering as well as in developing an understanding of the protein folding process. Such AFUs can also be used as model systems in order to study the structural organization of proteins.     

Protein docking prediction using predicted protein-protein interface

Background  

Many important cellular processes are carried out by protein complexes. To provide physical pictures of interacting proteins, many computational protein-protein prediction methods have been developed in the past. However, it is still difficult to identify the correct docking complex structure within top ranks among alternative conformations.