Identification of protein complexes from multi-relationship protein interaction networks

Background

Protein complexes play an important role in biological processes. Recent developments in experiments have resulted in the publication of many high-quality, large-scale protein-protein interaction (PPI) datasets, which provide abundant data for computational approaches to the prediction of protein complexes. However, the precision of protein complex prediction still needs to be improved due to the incompletion and noise in PPI networks.

Results

There exist complex and diverse relationships among proteins after integrating multiple sources of biological information. Considering that the influences of different types of interactions are not the same weight for protein complex prediction, we construct a multi-relationship protein interaction network (MPIN) by integrating PPI network topology with gene ontology annotation information. Then, we design a novel algorithm named MINE (identifying protein complexes based on Multi-relationship protein Interaction NEtwork) to predict protein complexes with high cohesion and low coupling from MPIN.

Conclusions

The experiments on yeast data show that MINE outperforms the current methods in terms of both accuracy and statistical significance.

     

A multi-network clustering method for detecting protein complexes from multiple heterogeneous networks

Background

The accurate identification of protein complexes is important for the understanding of cellular organization. Up to now, computational methods for protein complex detection are mostly focus on mining clusters from protein-protein interaction (PPI) networks. However, PPI data collected by high-throughput experimental techniques are known to be quite noisy. It is hard to achieve reliable prediction results by simply applying computational methods on PPI data. Behind protein interactions, there are protein domains that interact with each other. Therefore, based on domain-protein associations, the joint analysis of PPIs and domain-domain interactions (DDI) has the potential to obtain better performance in protein complex detection. As traditional computational methods are designed to detect protein complexes from a single PPI network, it is necessary to design a new algorithm that could effectively utilize the information inherent in multiple heterogeneous networks.

Results

In this paper, we introduce a novel multi-network clustering algorithm to detect protein complexes from multiple heterogeneous networks. Unlike existing protein complex identification algorithms that focus on the analysis of a single PPI network, our model can jointly exploit the information inherent in PPI and DDI data to achieve more reliable prediction results. Extensive experiment results on real-world data sets demonstrate that our method can predict protein complexes more accurately than other state-of-the-art protein complex identification algorithms.

Conclusions

In this work, we demonstrate that the joint analysis of PPI network and DDI network can help to improve the accuracy of protein complex detection.

     

Using indirect protein-protein interactions for protein complex prediction

Protein complexes are fundamental for understanding principles of cellular organizations. As the sizes of protein-protein interaction (PPI) networks are increasing, accurate and fast protein complex prediction from these PPI networks can serve as a guide for biological experiments to discover novel protein complexes. However, it is not easy to predict protein complexes from PPI networks, especially in situations where the PPI network is noisy and still incomplete. Here, we study the use of indirect interactions between level-2 neighbors (level-2 interactions) for protein complex prediction. We know from previous work that proteins which do not interact but share interaction partners (level-2 neighbors) often share biological functions. We have proposed a method in which all direct and indirect interactions are first weighted using topological weight (FS-Weight), which estimates the strength of functional association. Interactions with low weight are removed from the network, while level-2 interactions with high weight are introduced into the interaction network. Existing clustering algorithms can then be applied to this modified network. We have also proposed a novel algorithm that searches for cliques in the modified network, and merge cliques to form clusters using a "partial clique merging" method. Experiments show that (1) the use of indirect interactions and topological weight to augment protein-protein interactions can be used to improve the precision of clusters predicted by various existing clustering algorithms; and (2) our complex-finding algorithm performs very well on interaction networks modified in this way. Since no other information except the original PPI network is used, our approach would be very useful for protein complex prediction, especially for prediction of novel protein complexes.     

Protein complexes identification based on go attributed network embedding

Background

Identifying protein complexes from protein-protein interaction (PPI) network is one of the most important tasks in proteomics. Existing computational methods try to incorporate a variety of biological evidences to enhance the quality of predicted complexes. However, it is still a challenge to integrate different types of biological information into the complexes discovery process under a unified framework. Recently, attributed network embedding methods have be proved to be remarkably effective in generating vector representations for nodes in the network. In the transformed vector space, both the topological proximity and node attributed affinity between different nodes are preserved. Therefore, such attributed network embedding methods provide us a unified framework to integrate various biological evidences into the protein complexes identification process.

Results

In this article, we propose a new method called GANE to predict protein complexes based on Gene Ontology (GO) attributed network embedding. Firstly, it learns the vector representation for each protein from a GO attributed PPI network. Based on the pair-wise vector representation similarity, a weighted adjacency matrix is constructed. Secondly, it uses the clique mining method to generate candidate cores. Consequently, seed cores are obtained by ranking candidate cores based on their densities on the weighted adjacency matrix and removing redundant cores. For each seed core, its attachments are the proteins with correlation score that is larger than a given threshold. The combination of a seed core and its attachment proteins is reported as a predicted protein complex by the GANE algorithm. For performance evaluation, we compared GANE with six protein complex identification methods on five yeast PPI networks. Experimental results showes that GANE performs better than the competing algorithms in terms of different evaluation metrics.

Conclusions

GANE provides a framework that integrate many valuable and different biological information into the task of protein complex identification. The protein vector representation learned from our attributed PPI network can also be used in other tasks, such as PPI prediction and disease gene prediction.

     

Predicting protein functions from PPI networks using functional aggregation

Predicting protein functions computationally from massive protein-protein interaction (PPI) data generated by high-throughput technology is one of the challenges and fundamental problems in the post-genomic era. Although there have been many approaches developed for computationally predicting protein functions, the mutual correlations among proteins in terms of protein functions have not been thoroughly investigated and incorporated into existing prediction methods, especially in voting based prediction methods. In this paper, we propose an innovative method to predict protein functions from PPI data by aggregating the functional correlations among relevant proteins using the Choquet-Integral in fuzzy theory. This functional aggregation measures the real impact of each relevant protein function on the final prediction results, and reduces the impact of repeated functional information on the prediction. Accordingly, a new protein similarity and a new iterative prediction algorithm are proposed in this paper. The experimental evaluations on real PPI datasets demonstrate the effectiveness of our method.     

Iteration method for predicting essential proteins based on orthology and protein-protein interaction networks

ABSTRACT: BACKGROUND: Identification of essential proteins plays a significant role in understanding minimal requirements for the cellular survival and development. Many computational methods have been proposed for predicting essential proteins by using the topological features of protein-protein interaction (PPI) networks. However, most of these methods ignored intrinsic biological meaning of proteins. Moreover, PPI data contains many false positives and false negatives. To overcome these limitations, recently many research groups have started to focus on identification of essential proteins by integrating PPI networks with other biological information. However, none of their methods has widely been acknowledged. RESULTS: By considering the facts that essential proteins are more evolutionarily conserved than nonessential proteins and essential proteins frequently bind each other, we propose an iteration method for predicting essential proteins by integrating the orthology with PPI networks, named by ION. Differently from other methods, ION identifies essential proteins depending on not only the connections between proteins but also their orthologous properties and features of their neighbors. ION is implemented to predict essential proteins in S. cerevisiae. Experimental results show that ION can achieve higher identification accuracy than eight other existing centrality methods in terms of area under the curve (AUC). Moreover, ION identifies a large amount of essential proteins which have been ignored by eight other existing centrality methods because of their low-connectivity. Many proteins ranked in top 100 by ION are both essential and belong to the complexes with certain biological functions. Furthermore, no matter how many reference organisms were selected, ION outperforms all eight other existing centrality methods. While using as many as possible reference organisms can improve the performance of ION. Additionally, ION also shows good prediction performance in E.Coli K-12. CONCLUSIONS: The accuracy of predicting essential proteins can be improved by integrating the orthology with PPI networks.     

Protein Complex Identification by Integrating Protein-Protein Interaction Evidence from Multiple Sources

Background

Understanding protein complexes is important for understanding the science of cellular organization and function. Many computational methods have been developed to identify protein complexes from experimentally obtained protein-protein interaction (PPI) networks. However, interaction information obtained experimentally can be unreliable and incomplete. Reconstructing these PPI networks with PPI evidences from other sources can improve protein complex identification.

Results

We combined PPI information from 6 different sources and obtained a reconstructed PPI network for yeast through machine learning. Some popular protein complex identification methods were then applied to detect yeast protein complexes using the new PPI networks. Our evaluation indicates that protein complex identification algorithms using the reconstructed PPI network significantly outperform ones on experimentally verified PPI networks.

Conclusions

We conclude that incorporating PPI information from other sources can improve the effectiveness of protein complex identification.     

A computational model for predicting protein interactions based on multidomain collaboration

Recently, several domain-based computational models for predicting protein-protein interactions (PPIs) have been proposed. The conventional methods usually infer domain or domain combination (DC) interactions from already known interacting sets of proteins, and then predict PPIs using the information. However, the majority of these models often have limitations in providing detailed information on which domain pair (single domain interaction) or DC pair (multidomain interaction) will actually interact for the predicted protein interaction. Therefore, a more comprehensive and concrete computational model for the prediction of PPIs is needed. We developed a computational model to predict PPIs using the information of intraprotein domain cohesion and interprotein DC coupling interaction. A method of identifying the primary interacting DC pair was also incorporated into the model in order to infer actual participants in a predicted interaction. Our method made an apparent improvement in the PPI prediction accuracy, and the primary interacting DC pair identification was valid specifically in predicting multidomain protein interactions. In this paper, we demonstrate that 1) the intraprotein domain cohesion is meaningful in improving the accuracy of domain-based PPI prediction, 2) a prediction model incorporating the intradomain cohesion enables us to identify the primary interacting DC pair, and 3) a hybrid approach using the intra/interdomain interaction information can lead to a more accurate prediction.     

Detection of protein complexes using a protein ranking algorithm

Detecting protein complexes from protein‐protein interaction (PPI) network is becoming a difficult challenge in computational biology. There is ample evidence that many disease mechanisms involve protein complexes, and being able to predict these complexes is important to the characterization of the relevant disease for diagnostic and treatment purposes. This article introduces a novel method for detecting protein complexes from PPI by using a protein ranking algorithm (ProRank). ProRank quantifies the importance of each protein based on the interaction structure and the evolutionarily relationships between proteins in the network. A novel way of identifying essential proteins which are known for their critical role in mediating cellular processes and constructing protein complexes is proposed and analyzed. We evaluate the performance of ProRank using two PPI networks on two reference sets of protein complexes created from Munich Information Center for Protein Sequence, containing 81 and 162 known complexes, respectively. We compare the performance of ProRank to some of the well known protein complex prediction methods (ClusterONE, CMC, CFinder, MCL, MCode and Core) in terms of precision and recall. We show that ProRank predicts more complexes correctly at a competitive level of precision and recall. The level of the accuracy achieved using ProRank in comparison to other recent methods for detecting protein complexes is a strong argument in favor of the proposed method. Proteins 2012;. © 2012 Wiley Periodicals, Inc.     

Protein complex prediction via cost-based clustering

MOTIVATION: Understanding principles of cellular organization and function can be enhanced if we detect known and predict still undiscovered protein complexes within the cell's protein-protein interaction (PPI) network. Such predictions may be used as an inexpensive tool to direct biological experiments. The increasing amount of available PPI data necessitates an accurate and scalable approach to protein complex identification. RESULTS: We have developed the Restricted Neighborhood Search Clustering Algorithm (RNSC) to efficiently partition networks into clusters using a cost function. We applied this cost-based clustering algorithm to PPI networks of Saccharomyces cerevisiae, Drosophila melanogaster and Caenorhabditis elegans to identify and predict protein complexes. We have determined functional and graph-theoretic properties of true protein complexes from the MIPS database. Based on these properties, we defined filters to distinguish between identified network clusters and true protein complexes. Conclusions: Our application of the cost-based clustering algorithm provides an accurate and scalable method of detecting and predicting protein complexes within a PPI network.     

Detecting temporal protein complexes from dynamic protein-protein interaction networks

Background

Proteins dynamically interact with each other to perform their biological functions. The dynamic operations of protein interaction networks (PPI) are also reflected in the dynamic formations of protein complexes. Existing protein complex detection algorithms usually overlook the inherent temporal nature of protein interactions within PPI networks. Systematically analyzing the temporal protein complexes can not only improve the accuracy of protein complex detection, but also strengthen our biological knowledge on the dynamic protein assembly processes for cellular organization.

Results

In this study, we propose a novel computational method to predict temporal protein complexes. Particularly, we first construct a series of dynamic PPI networks by joint analysis of time-course gene expression data and protein interaction data. Then a Time Smooth Overlapping Complex Detection model (TS-OCD) has been proposed to detect temporal protein complexes from these dynamic PPI networks. TS-OCD can naturally capture the smoothness of networks between consecutive time points and detect overlapping protein complexes at each time point. Finally, a nonnegative matrix factorization based algorithm is introduced to merge those very similar temporal complexes across different time points.

Conclusions

Extensive experimental results demonstrate the proposed method is very effective in detecting temporal protein complexes than the state-of-the-art complex detection techniques.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-335) contains supplementary material, which is available to authorized users.     

Deciphering protein-protein interactions. Part II. Computational methods to predict protein and domain interaction partners

Recent advances in high-throughput experimental methods for the identification of protein interactions have resulted in a large amount of diverse data that are somewhat incomplete and contradictory. As valuable as they are, such experimental approaches studying protein interactomes have certain limitations that can be complemented by the computational methods for predicting protein interactions. In this review we describe different approaches to predict protein interaction partners as well as highlight recent achievements in the prediction of specific domains mediating protein-protein interactions. We discuss the applicability of computational methods to different types of prediction problems and point out limitations common to all of them.     

Computational Prediction of Protein–Protein Interactions

Recently a number of computational approaches have been developed for the prediction of protein–protein interactions. Complete genome sequencing projects have provided the vast amount of information needed for these analyses. These methods utilize the structural, genomic, and biological context of proteins and genes in complete genomes to predict protein interaction networks and functional linkages between proteins. Given that experimental techniques remain expensive, time-consuming, and labor-intensive, these methods represent an important advance in proteomics. Some of these approaches utilize sequence data alone to predict interactions, while others combine multiple computational and experimental datasets to accurately build protein interaction maps for complete genomes. These methods represent a complementary approach to current high-throughput projects whose aim is to delineate protein interaction maps in complete genomes. We will describe a number of computational protocols for protein interaction prediction based on the structural, genomic, and biological context of proteins in complete genomes, and detail methods for protein interaction network visualization and analysis.     

A Novel Core‐Attachment–Based Method to Identify Dynamic Protein Complexes Based on Gene Expression Profiles and PPI Networks

Cellular functions are always performed by protein complexes. At present, many approaches have been proposed to identify protein complexes from protein–protein interaction (PPI) networks. Some approaches focus on detecting local dense subgraphs in PPI networks which are regarded as protein‐complex cores, then identify protein complexes by including local neighbors. However, from gene expression profiles at different time points or tissues it is known that proteins are dynamic. Therefore, identifying dynamic protein complexes should become very important and meaningful. In this study, a novel core‐attachment–based method named CO‐DPC to detect dynamic protein complexes is presented. First, CO‐DPC selects active proteins according to gene expression profiles and the 3‐sigma principle, and constructs dynamic PPI networks based on the co‐expression principle and PPI networks. Second, CO‐DPC detects local dense subgraphs as the cores of protein complexes and then attach close neighbors of these cores to form protein complexes. In order to evaluate the method, the method and the existing algorithms are applied to yeast PPI networks. The experimental results show that CO‐DPC performs much better than the existing methods. In addition, the identified dynamic protein complexes can match very well and thus become more meaningful for future biological study.     

Functional topology in a network of protein interactions

MOTIVATION: The building blocks of biological networks are individual protein-protein interactions (PPIs). The cumulative PPI data set in Saccharomyces cerevisiae now exceeds 78 000. Studying the network of these interactions will provide valuable insight into the inner workings of cells. RESULTS: We performed a systematic graph theory-based analysis of this PPI network to construct computational models for describing and predicting the properties of lethal mutations and proteins participating in genetic interactions, functional groups, protein complexes and signaling pathways. Our analysis suggests that lethal mutations are not only highly connected within the network, but they also satisfy an additional property: their removal causes a disruption in network structure. We also provide evidence for the existence of alternate paths that bypass viable proteins in PPI networks, while such paths do not exist for lethal mutations. In addition, we show that distinct functional classes of proteins have differing network properties. We also demonstrate a way to extract and iteratively predict protein complexes and signaling pathways. We evaluate the power of predictions by comparing them with a random model, and assess accuracy of predictions by analyzing their overlap with MIPS database. CONCLUSIONS: Our models provide a means for understanding the complex wiring underlying cellular function, and enable us to predict essentiality, genetic interaction, function, protein complexes and cellular pathways. This analysis uncovers structure-function relationships observable in a large PPI network.     

Recent advances in predicting protein–protein interactions with the aid of artificial intelligence algorithms

Protein–protein interactions (PPIs) are essential in the regulation of biological functions and cell events, therefore understanding PPIs have become a key issue to understanding the molecular mechanism and investigating the design of drugs. Here we highlight the major developments in computational methods developed for predicting PPIs by using types of artificial intelligence algorithms. The first part introduces the source of experimental PPI data. The second part is devoted to the PPI prediction methods based on sequential information. The third part covers representative methods using structural information as the input feature. The last part is methods designed by combining different types of features. For each part, the state-of-the-art computational PPI prediction methods are reviewed in an inclusive view. Finally, we discuss the flaws existing in this area and future directions of next-generation algorithms.     

An efficient method for protein function annotation based on multilayer protein networks

Background

Accurate annotation of protein functions is still a big challenge for understanding life in the post-genomic era. Many computational methods based on protein-protein interaction (PPI) networks have been proposed to predict the function of proteins. However, the precision of these predictions still needs to be improved, due to the incompletion and noise in PPI networks. Integrating network topology and biological information could improve the accuracy of protein function prediction and may also lead to the discovery of multiple interaction types between proteins. Current algorithms generate a single network, which is archived using a weighted sum of all types of protein interactions.

Method

The influences of different types of interactions on the prediction of protein functions are not the same. To address this, we construct multilayer protein networks (MPN) by integrating PPI networks, the domain of proteins, and information on protein complexes. In the MPN, there is more than one type of connections between pairwise proteins. Different types of connections reflect different roles and importance in protein function prediction. Based on the MPN, we propose a new protein function prediction method, named function prediction based on multilayer protein networks (FP-MPN). Given an un-annotated protein, the FP-MPN method visits each layer of the MPN in turn and generates a set of candidate neighbors with known functions. A set of predicted functions for the testing protein is then formed and all of these functions are scored and sorted. Each layer plays different importance on the prediction of protein functions. A number of top-ranking functions are selected to annotate the unknown protein.

Conclusions

The method proposed in this paper was a better predictor when used on Saccharomyces cerevisiae protein data than other function prediction methods previously used. The proposed FP-MPN method takes different roles of connections in protein function prediction into account to reduce the artificial noise by introducing biological information.

     

Exploiting multi-layered information to iteratively predict protein functions

BackgroundSimilarity based computational methods are a useful tool for predicting protein functions from protein–protein interaction (PPI) datasets. Although various similarity-based prediction algorithms have been proposed, unsatisfactory prediction results have occurred on many occasions. The purpose of this type of algorithm is to predict functions of an unannotated protein from the functions of those proteins that are similar to the unannotated protein. Therefore, the prediction quality largely depends on how to select a set of proper proteins (i.e., a prediction domain) from which the functions of an unannotated protein are predicted, and how to measure the similarity between proteins. Another issue with existing algorithms is they only believe the function prediction is a one-off procedure, ignoring the fact that interactions amongst proteins are mutual and dynamic in terms of similarity when predicting functions. How to resolve these major issues to increase prediction quality remains a challenge in computational biology.ResultsIn this paper, we propose an innovative approach to predict protein functions of unannotated proteins iteratively from a PPI dataset. The iterative approach takes into account the mutual and dynamic features of protein interactions when predicting functions, and addresses the issues of protein similarity measurement and prediction domain selection by introducing into the prediction algorithm a new semantic protein similarity and a method of selecting the multi-layer prediction domain. The new protein similarity is based on the multi-layered information carried by protein functions. The evaluations conducted on real protein interaction datasets demonstrated that the proposed iterative function prediction method outperformed other similar or non-iterative methods, and provided better prediction results.ConclusionsThe new protein similarity derived from multi-layered information of protein functions more reasonably reflects the intrinsic relationships among proteins, and significant improvement to the prediction quality can occur through incorporation of mutual and dynamic features of protein interactions into the prediction algorithm.     

CPredictor3.0: detecting protein complexes from PPI networks with expression data and functional annotations

Background

Effectively predicting protein complexes not only helps to understand the structures and functions of proteins and their complexes, but also is useful for diagnosing disease and developing new drugs. Up to now, many methods have been developed to detect complexes by mining dense subgraphs from static protein-protein interaction (PPI) networks, while ignoring the value of other biological information and the dynamic properties of cellular systems.

Results

In this paper, based on our previous works CPredictor and CPredictor2.0, we present a new method for predicting complexes from PPI networks with both gene expression data and protein functional annotations, which is called CPredictor3.0. This new method follows the viewpoint that proteins in the same complex should roughly have similar functions and are active at the same time and place in cellular systems. We first detect active proteins by using gene express data of different time points and cluster proteins by using gene ontology (GO) functional annotations, respectively. Then, for each time point, we do set intersections with one set corresponding to active proteins generated from expression data and the other set corresponding to a protein cluster generated from functional annotations. Each resulting unique set indicates a cluster of proteins that have similar function(s) and are active at that time point. Following that, we map each cluster of active proteins of similar function onto a static PPI network, and get a series of induced connected subgraphs. We treat these subgraphs as candidate complexes. Finally, by expanding and merging these candidate complexes, the predicted complexes are obtained.We evaluate CPredictor3.0 and compare it with a number of existing methods on several PPI networks and benchmarking complex datasets. The experimental results show that CPredictor3.0 achieves the highest F1-measure, which indicates that CPredictor3.0 outperforms these existing method in overall.

Conclusion

CPredictor3.0 can serve as a promising tool of protein complex prediction.

     

Fully automated protein complex prediction based on topological similarity and community structure

To understand the function of protein complexes and their association with biological processes, a lot of studies have been done towards analyzing the protein-protein interaction (PPI) networks. However, the advancement in high-throughput technology has resulted in a humongous amount of data for analysis. Moreover, high level of noise, sparseness, and skewness in degree distribution of PPI networks limits the performance of many clustering algorithms and further analysis of their interactions.In addressing and solving these problems we present a novel random walk based algorithm that converts the incomplete and binary PPI network into a protein-protein topological similarity matrix (PP-TS matrix). We believe that if two proteins share some high-order topological similarities they are likely to be interacting with each other. Using the obtained PP-TS matrix, we constructed and used weighted networks to further study and analyze the interaction among proteins. Specifically, we applied a fully automated community structure finding algorithm (Auto-HQcut) on the obtained weighted network to cluster protein complexes. We then analyzed the protein complexes for significance in biological processes. To help visualize and analyze these protein complexes we also developed an interface that displays the resulting complexes as well as the characteristics associated with each complex.Applying our approach to a yeast protein-protein interaction network, we found that the predicted protein-protein interaction pairs with high topological similarities have more significant biological relevance than the original protein-protein interactions pairs. When we compared our PPI network reconstruction algorithm with other existing algorithms using gene ontology and gene co-expression, our algorithm produced the highest similarity scores. Also, our predicted protein complexes showed higher accuracy measure compared to the other protein complex predictions.