Computational Prediction Of Protein-protein Interactions Research Articles

Software and Databases for Protein-Protein Docking.

Protein-protein interactions (PPIs) provide valuable insights for understanding the principles of biological systems and for elucidating causes of incurable diseases. One of the techniques used for computational prediction of PPIs is protein-protein docking calculations, and a variety of software has been developed. This chapter is a summary of software and databases used for protein-protein docking.

Benchmark Evaluation of Protein-Protein Interaction Prediction Algorithms.

Protein–protein interactions (PPIs) perform various functions and regulate processes throughout cells. Knowledge of the full network of PPIs is vital to biomedical research, but most of the PPIs are still unknown. As it is infeasible to discover all of them experimentally due to technical and resource limitations, computational prediction of PPIs is essential and accurately assessing the performance of algorithms is required before further application or translation. However, many published methods compose their evaluation datasets incorrectly, using a higher proportion of positive class data than occuring naturally, leading to exaggerated performance. We re-implemented various published algorithms and evaluated them on datasets with realistic data compositions and found that their performance is overstated in original publications; with several methods outperformed by our control models built on ‘illogical’ and random number features. We conclude that these methods are influenced by an over-characterization of some proteins in the literature and due to scale-free nature of PPI network and that they fail when tested on all possible protein pairs. Additionally, we found that sequence-only-based algorithms performed worse than those that employ functional and expression features. We present a benchmark evaluation of many published algorithms for PPI prediction. The source code of our implementations and the benchmark datasets created here are made available in open source.

Deep Learning for Protein-Protein Interaction Site Prediction.

Protein-protein interactions (PPIs) are central to cellular functions. Experimental methods for predicting PPIs are well developed but are time and resource expensive and suffer from high false-positive error rates at scale. Computational prediction of PPIs is highly desirable for a mechanistic understanding of cellular processes and offers the potential to identify highly selective drug targets. In this chapter, details of developing a deep learning approach to predicting which residues in a protein are involved in forming a PPI-a task known as PPI site prediction-are outlined. The key decisions to be made in defining a supervised machine learning project in this domain are here highlighted. Alternative training regimes for deep learning models to address shortcomings in existing approaches and provide starting points for further research are discussed. This chapter is written to serve as a companion to developing deep learning approaches to protein-protein interaction site prediction, and an introduction to developing geometric deep learning projects operating on protein structure graphs.

Evolution of Sequence-based Bioinformatics Tools for Protein-protein Interaction Prediction.

Protein-protein interactions (PPIs) are the physical connections between two or more proteins via electrostatic forces or hydrophobic effects. Identification of the PPIs is pivotal, which contributes to many biological processes including protein function, disease incidence, and therapy design. The experimental identification of PPIs via high-throughput technology is time-consuming and expensive. Bioinformatics approaches are expected to solve such restrictions. In this review, our main goal is to provide an inclusive view of the existing sequence-based computational prediction of PPIs. Initially, we briefly introduce the currently available PPI databases and then review the state-of-the-art bioinformatics approaches, working principles, and their performances. Finally, we discuss the caveats and future perspective of the next generation algorithms for the prediction of PPIs.

Dimensionality Reduction Techniques in the Computational Prediction of Protein-Protein Interactions: Classical versus Sophisticated New Techniques

Dimensionality Reduction Techniques in the Computational Prediction of Protein-Protein Interactions: Classical versus Sophisticated New Techniques

IAS: Interaction Specific GO Term Associations for Predicting Protein-Protein Interaction Networks.

Proteins carry out their function in a cell through interactions with other proteins. A large scale protein-protein interaction (PPI) network of an organism provides static yet an essential structure of interactions, which is valuable clue for understanding the functions of proteins and pathways. PPIs are determined primarily by experimental methods; however, computational PPI prediction methods can supplement or verify PPIs identified by experiment. Here, we developed a novel scoring method for predicting PPIs from Gene Ontology (GO) annotations of proteins. Unlike existing methods that consider functional similarity as an indication of interaction between proteins, the new score, named the protein-protein Interaction Association Score (IAS), was computed from GO term associations of known interacting protein pairs in 49 organisms. IAS was evaluated on PPI data of six organisms and found to outperform existing GO term-based scoring methods. Moreover, consensus scoring methods that combine different scores further improved performance of PPI prediction.

Predicting Protein-Protein Interactions from Primary Protein Sequences Using a Novel Multi-Scale Local Feature Representation Scheme and the Random Forest

The study of protein-protein interactions (PPIs) can be very important for the understanding of biological cellular functions. However, detecting PPIs in the laboratories are both time-consuming and expensive. For this reason, there has been much recent effort to develop techniques for computational prediction of PPIs as this can complement laboratory procedures and provide an inexpensive way of predicting the most likely set of interactions at the entire proteome scale. Although much progress has already been achieved in this direction, the problem is still far from being solved. More effective approaches are still required to overcome the limitations of the current ones. In this study, a novel Multi-scale Local Descriptor (MLD) feature representation scheme is proposed to extract features from a protein sequence. This scheme can capture multi-scale local information by varying the length of protein-sequence segments. Based on the MLD, an ensemble learning method, the Random Forest (RF) method, is used as classifier. The MLD feature representation scheme facilitates the mining of interaction information from multi-scale continuous amino acid segments, making it easier to capture multiple overlapping continuous binding patterns within a protein sequence. When the proposed method is tested with the PPI data of Saccharomyces cerevisiae, it achieves a prediction accuracy of 94.72% with 94.34% sensitivity at the precision of 98.91%. Extensive experiments are performed to compare our method with existing sequence-based method. Experimental results show that the performance of our predictor is better than several other state-of-the-art predictors also with the H. pylori dataset. The reason why such good results are achieved can largely be credited to the learning capabilities of the RF model and the novel MLD feature representation scheme. The experiment results show that the proposed approach can be very promising for predicting PPIs and can be a useful tool for future proteomic studies.

Plant Comparative and Functional Genomics.

Plant Comparative and Functional Genomics.

LocFuse: Human protein–protein interaction prediction via classifier fusion using protein localization information

Protein–protein interaction (PPI) detection is one of the central goals of functional genomics and systems biology. Knowledge about the nature of PPIs can help fill the widening gap between sequence information and functional annotations. Although experimental methods have produced valuable PPI data, they also suffer from significant limitations. Computational PPI prediction methods have attracted tremendous attentions. Despite considerable efforts, PPI prediction is still in its infancy in complex multicellular organisms such as humans. Here, we propose a novel ensemble learning method, LocFuse, which is useful in human PPI prediction. This method uses eight different genomic and proteomic features along with four types of different classifiers. The prediction performance of this classifier selection method was found to be considerably better than methods employed hitherto. This confirms the complex nature of the PPI prediction problem and also the necessity of using biological information for classifier fusion. The LocFuse is available at: http://lbb.ut.ac.ir/Download/LBBsoft/LocFuse. Biological significanceThe results revealed that if we divide proteome space according to the cellular localization of proteins, then the utility of some classifiers in PPI prediction can be improved. Therefore, to predict the interaction for any given protein pair, we can select the most accurate classifier with regard to the cellular localization information. Based on the results, we can say that the importance of different features for PPI prediction varies between differently localized proteins; however in general, our novel features, which were extracted from position-specific scoring matrices (PSSMs), are the most important ones and the Random Forest (RF) classifier performs best in most cases. LocFuse was developed with a user-friendly graphic interface and it is freely available for Linux, Mac OSX and MS Windows operating systems.

Transient protein-protein interface prediction: datasets, features, algorithms, and the RAD-T predictor

BackgroundTransient protein-protein interactions (PPIs), which underly most biological processes, are a prime target for therapeutic development. Immense progress has been made towards computational prediction of PPIs using methods such as protein docking and sequence analysis. However, docking generally requires high resolution structures of both of the binding partners and sequence analysis requires that a significant number of recurrent patterns exist for the identification of a potential binding site. Researchers have turned to machine learning to overcome some of the other methods’ restrictions by generalising interface sites with sets of descriptive features. Best practices for dataset generation, features, and learning algorithms have not yet been identified or agreed upon, and an analysis of the overall efficacy of machine learning based PPI predictors is due, in order to highlight potential areas for improvement.ResultsThe presence of unknown interaction sites as a result of limited knowledge about protein interactions in the testing set dramatically reduces prediction accuracy. Greater accuracy in labelling the data by enforcing higher interface site rates per domain resulted in an average 44% improvement across multiple machine learning algorithms. A set of 10 biologically unrelated proteins that were consistently predicted on with high accuracy emerged through our analysis. We identify seven features with the most predictive power over multiple datasets and machine learning algorithms. Through our analysis, we created a new predictor, RAD-T, that outperforms existing non-structurally specializing machine learning protein interface predictors, with an average 59% increase in MCC score on a dataset with a high number of interactions.ConclusionCurrent methods of evaluating machine-learning based PPI predictors tend to undervalue their performance, which may be artificially decreased by the presence of un-identified interaction sites. Changes to predictors’ training sets will be integral to the future progress of interface prediction by machine learning methods. We reveal the need for a larger test set of well studied proteins or domain-specific scoring algorithms to compensate for poor interaction site identification on proteins in general.

Predicting whole genome protein interaction networks from primary sequence data in model and non-model organisms using ENTS

BackgroundThe large-scale identification of physical protein-protein interactions (PPIs) is an important step toward understanding how biological networks evolve and generate emergent phenotypes. However, experimental identification of PPIs is a laborious and error-prone process, and current methods of PPI prediction tend to be highly conservative or require large amounts of functional data that may not be available for newly-sequenced organisms.ResultsIn this study we demonstrate a random-forest based technique, ENTS, for the computational prediction of protein-protein interactions based only on primary sequence data. Our approach is able to efficiently predict interactions on a whole-genome scale for any eukaryotic organism, using pairwise combinations of conserved domains and predicted subcellular localization of proteins as input features. We present the first predicted interactome for the forest tree Populus trichocarpa in addition to the predicted interactomes for Saccharomyces cerevisiae, Homo sapiens, Mus musculus, and Arabidopsis thaliana. Comparing our approach to other PPI predictors, we find that ENTS performs comparably to or better than a number of existing approaches, including several that utilize a variety of functional information for their predictions. We also find that the predicted interactions are biologically meaningful, as indicated by similarity in functional annotations and enrichment of co-expressed genes in public microarray datasets. Furthermore, we demonstrate some of the biological insights that can be gained from these predicted interaction networks. We show that the predicted interactions yield informative groupings of P. trichocarpa metabolic pathways, literature-supported associations among human disease states, and theory-supported insight into the evolutionary dynamics of duplicated genes in paleopolyploid plants.ConclusionWe conclude that the ENTS classifier will be a valuable tool for the de novo annotation of genome sequences, providing initial clues about regulatory and metabolic network topology, and revealing relationships that are not immediately obvious from traditional homology-based annotations.

Computational Prediction of Protein-Protein Interactions in Leishmania Predicted Proteomes

The Trypanosomatids parasites Leishmania braziliensis, Leishmania major and Leishmania infantum are important human pathogens. Despite of years of study and genome availability, effective vaccine has not been developed yet, and the chemotherapy is highly toxic. Therefore, it is clear just interdisciplinary integrated studies will have success in trying to search new targets for developing of vaccines and drugs. An essential part of this rationale is related to protein-protein interaction network (PPI) study which can provide a better understanding of complex protein interactions in biological system. Thus, we modeled PPIs for Trypanosomatids through computational methods using sequence comparison against public database of protein or domain interaction for interaction prediction (Interolog Mapping) and developed a dedicated combined system score to address the predictions robustness. The confidence evaluation of network prediction approach was addressed using gold standard positive and negative datasets and the AUC value obtained was 0.94. As result, 39,420, 43,531 and 45,235 interactions were predicted for L. braziliensis, L. major and L. infantum respectively. For each predicted network the top 20 proteins were ranked by MCC topological index. In addition, information related with immunological potential, degree of protein sequence conservation among orthologs and degree of identity compared to proteins of potential parasite hosts was integrated. This information integration provides a better understanding and usefulness of the predicted networks that can be valuable to select new potential biological targets for drug and vaccine development. Network modularity which is a key when one is interested in destabilizing the PPIs for drug or vaccine purposes along with multiple alignments of the predicted PPIs were performed revealing patterns associated with protein turnover. In addition, around 50% of hypothetical protein present in the networks received some degree of functional annotation which represents an important contribution since approximately 60% of Leishmania predicted proteomes has no predicted function.

Human protein–protein interaction prediction by a novel sequence-based co-evolution method: co-evolutionary divergence

Protein-protein interaction (PPI) plays an important role in understanding gene functions, and many computational PPI prediction methods have been proposed in recent years. Despite the extensive efforts, PPI prediction still has much room to improve. Sequence-based co-evolution methods include the substitution rate method and the mirror tree method, which compare sequence substitution rates and topological similarity of phylogenetic trees, respectively. Although they have been used to predict PPI in species with small genomes like Escherichia coli, such methods have not been tested in large scale proteome like Homo sapiens. In this study, we propose a novel sequence-based co-evolution method, co-evolutionary divergence (CD), for human PPI prediction. Built on the basic assumption that protein pairs with similar substitution rates are likely to interact with each other, the CD method converts the evolutionary information from 14 species of vertebrates into likelihood ratios and combined them together to infer PPI. We showed that the CD method outperformed the mirror tree method in three independent human PPI datasets by a large margin. With the arrival of more species genome information generated by next generation sequencing, the performance of the CD method can be further improved. Source code and support are available at http://mib.stat.sinica.edu.tw/LAP/tmp/CD.rar.

Computational Prediction of Protein-Protein Interactions of Human Tyrosinase

The various studies on tyrosinase have recently gained the attention of researchers due to their potential application values and the biological functions. In this study, we predicted the 3D structure of human tyrosinase and simulated the protein-protein interactions between tyrosinase and three binding partners, four and half LIM domains 2 (FHL2), cytochrome b-245 alpha polypeptide (CYBA), and RNA-binding motif protein 9 (RBM9). Our interaction simulations showed significant binding energy scores of −595.3 kcal/mol for FHL2, −859.1 kcal/mol for CYBA, and −821.3 kcal/mol for RBM9. We also investigated the residues of each protein facing toward the predicted site of interaction with tyrosinase. Our computational predictions will be useful for elucidating the protein-protein interactions of tyrosinase and studying its binding mechanisms.

Incorporating multiple genomic features with the utilization of interacting domain patterns to improve the prediction of protein–protein interactions

Protein–protein interaction (PPI) networks play an outstanding role in the organization of life. Parallel to the growth of experimental techniques on determining PPIs, the emergence of computational methods has greatly accelerated the time needed for the identification of PPIs on a wide genomic scale. Although experimental approaches have limitations that can be complemented by the computational methods, the results from computational methods still suffer from high false positive rates which contribute to the lack of solid PPI information. Our study introduces the PPI-Filter; a computational framework aimed at improving PPI prediction results. It is a post-prediction process which involves filtration, using information based on three different genomic features; (i) gene ontology annotation (GOA), (ii) homologous interactions and (iii) protein families (PFAM) domain interactions. In the study, we incorporated a protein function prediction method, based on interacting domain patterns, the protein function predictor or PFP (), for the purpose of aiding the GOA. The goal is to improve the robustness of predicted PPI pairs by removing the false positive pairs and sustaining as much true positive pairs as possible, thus achieving a high confidence level of PPI datasets. The PPI-Filter has been proven to be applicable based on the satisfactory results obtained using signal-to-noise ratio (SNR) and strength measurements that were applied on different computational PPI prediction methods.

Amino-Acid Residue Association Models for Large Scale Protein-Protein Interaction Prediction

The computational prediction of protein-protein interactions (PPI) is an essential complement to direct experimental evidence. Traditional approaches rely on less available or computationally predicted surface properties, show database-specific performances and are computationally expensive for large-scale datasets. Several sensitivity and specificity issues remain. Here, we report a novel method based on 'Amino-acid Residue Associations' (ARA) among interacting proteins which utilizes the accurate and easily available primary sequence. Large scale PPI datasets for six model species (from E. coli to human) were studied. The ARA method shows up to 73%sensitivity and 78% specificity. Furthermore, the method performs remarkably well in terms of stability and generalizability. The performance of ARA method benchmarked against existing prediction techniques shows performance improvement upto 25%. Ability of ARA method to predict PPI across species and across databases is also demonstrated. Overall, the ARA method provides a significant improvement over existing ones in correctly identifying large scale protein-protein interactions,irrespective of the data resource, network size or organism. The MATLAB code for ARA approach will be made available upon request.

Computational Approaches for Predicting Protein–Protein Interactions: A Survey

Discovery of the protein interactions that take place within a cell can provide a starting point for understanding biological regulatory pathways. Global interaction patterns among proteins, for example, can suggest new drug targets and aid the design of new drugs by providing a clearer picture of the biological pathways in the neighborhoods of the drug targets. High-throughput experimental screens have been developed to detect protein-protein interactions, however, they show high rates of errors in terms of false positives and false negatives. Many computational approaches have been proposed to tackle the problem of protein-protein interaction prediction. They range from comparative genomics based methods to data integration based approaches. Challenging properties of protein-protein interaction data have to be addressed appropriately before a higher quality interaction map with better coverage can be achieved. This paper presents a survey of major works in computational prediction of protein-protein interactions, explaining their assumptions, main ideas, and limitations.

Coevolution of gene expression among interacting proteins.

Physically interacting proteins or parts of proteins are expected to evolve in a coordinated manner that preserves proper interactions. Such coevolution at the amino acid-sequence level is well documented and has been used to predict interacting proteins, domains, and amino acids. Interacting proteins are also often precisely coexpressed with one another, presumably to maintain proper stoichiometry among interacting components. Here, we show that the expression levels of physically interacting proteins coevolve. We estimate average expression levels of genes from four closely related fungi of the genus Saccharomyces using the codon adaptation index and show that expression levels of interacting proteins exhibit coordinated changes in these different species. We find that this coevolution of expression is a more powerful predictor of physical interaction than is coevolution of amino acid sequence. These results demonstrate that gene expression levels can coevolve, adding another dimension to the study of the coevolution of interacting proteins and underscoring the importance of maintaining coexpression of interacting proteins over evolutionary time. Our results also suggest that expression coevolution can be used for computational prediction of protein-protein interactions.