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.     

Discovering protein complexes in protein interaction networks via exploring the weak ties effect

Background

Studying protein complexes is very important in biological processes since it helps reveal the structure-functionality relationships in biological networks and much attention has been paid to accurately predict protein complexes from the increasing amount of protein-protein interaction (PPI) data. Most of the available algorithms are based on the assumption that dense subgraphs correspond to complexes, failing to take into account the inherence organization within protein complex and the roles of edges. Thus, there is a critical need to investigate the possibility of discovering protein complexes using the topological information hidden in edges.

Results

To provide an investigation of the roles of edges in PPI networks, we show that the edges connecting less similar vertices in topology are more significant in maintaining the global connectivity, indicating the weak ties phenomenon in PPI networks. We further demonstrate that there is a negative relation between the weak tie strength and the topological similarity. By using the bridges, a reliable virtual network is constructed, in which each maximal clique corresponds to the core of a complex. By this notion, the detection of the protein complexes is transformed into a classic all-clique problem. A novel core-attachment based method is developed, which detects the cores and attachments, respectively. A comprehensive comparison among the existing algorithms and our algorithm has been made by comparing the predicted complexes against benchmark complexes.

Conclusions

We proved that the weak tie effect exists in the PPI network and demonstrated that the density is insufficient to characterize the topological structure of protein complexes. Furthermore, the experimental results on the yeast PPI network show that the proposed method outperforms the state-of-the-art algorithms. The analysis of detected modules by the present algorithm suggests that most of these modules have well biological significance in context of complexes, suggesting that the roles of edges are critical in discovering protein complexes.

     

Identification of core-attachment complexes based on maximal frequent patterns in protein-protein interaction networks

In this paper, we present a method for core-attachment complexes identification based on maximal frequent patterns (CCiMFP) in yeast protein-protein interaction (PPI) networks. First, we detect subgraphs with high degree as candidate protein cores by mining maximal frequent patterns. Then using topological and functional similarities, we combine highly similar protein cores and filter insignificant ones. Finally, the core-attachment complexes are formed by adding attachment proteins to each significant core. We experimentally evaluate the performance of our method CCiMFP on yeast PPI networks. Using gold standard sets of protein complexes, Gene Ontology (GO), and localization annotations, we show that our method gains an improvement over the previous algorithms in terms of precision, recall, and biological significance of the predicted complexes. The colocalization scores of our predicted complex sets are higher than those of two known complex sets. Moreover, our method can detect GO-enriched complexes with disconnected cores compared with other methods based on the subgraph connectivity.     

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.

     

Integrating domain similarity to improve protein complexes identification in TAP-MS data

Background

Detecting protein complexes in protein-protein interaction (PPI) networks plays an important role in improving our understanding of the dynamic of cellular organisation. However, protein interaction data generated by high-throughput experiments such as yeast-two-hybrid (Y2H) and tandem affinity-purification/mass-spectrometry (TAP-MS) are characterised by the presence of a significant number of false positives and false negatives. In recent years there has been a growing trend to incorporate diverse domain knowledge to support large-scale analysis of PPI networks.

Methods

This paper presents a new algorithm, by incorporating Gene Ontology (GO) based semantic similarities, to detect protein complexes from PPI networks generated by TAP-MS. By taking co-complex relations in TAP-MS data into account, TAP-MS PPI networks are modelled as bipartite graph, where bait proteins consist of one set of nodes and prey proteins are on the other. Similarities between pairs of bait proteins are computed by considering both the topological features and GO-driven semantic similarities. Bait proteins are then grouped in to sets of clusters based on their pair-wise similarities to produce a set of 'seed' clusters. An expansion process is applied to each 'seed' cluster to recruit prey proteins which are significantly associated with the same set of bait proteins. Thus, completely identified protein complexes are then obtained.

Results

The proposed algorithm has been applied to real TAP-MS PPI networks. Fifteen quality measures have been employed to evaluate the quality of generated protein complexes. Experimental results show that the proposed algorithm has greatly improved the accuracy of identifying complexes and outperformed several state-of-the-art clustering algorithms. Moreover, by incorporating semantic similarity, the proposed algorithm is more robust to noises in the networks.

     

Pairwise alignment of protein interaction networks.

With an ever-increasing amount of available data on protein-protein interaction (PPI) networks and research revealing that these networks evolve at a modular level, discovery of conserved patterns in these networks becomes an important problem. Although available data on protein-protein interactions is currently limited, recently developed algorithms have been shown to convey novel biological insights through employment of elegant mathematical models. The main challenge in aligning PPI networks is to define a graph theoretical measure of similarity between graph structures that captures underlying biological phenomena accurately. In this respect, modeling of conservation and divergence of interactions, as well as the interpretation of resulting alignments, are important design parameters. In this paper, we develop a framework for comprehensive alignment of PPI networks, which is inspired by duplication/divergence models that focus on understanding the evolution of protein interactions. We propose a mathematical model that extends the concepts of match, mismatch, and gap in sequence alignment to that of match, mismatch, and duplication in network alignment and evaluates similarity between graph structures through a scoring function that accounts for evolutionary events. By relying on evolutionary models, the proposed framework facilitates interpretation of resulting alignments in terms of not only conservation but also divergence of modularity in PPI networks. Furthermore, as in the case of sequence alignment, our model allows flexibility in adjusting parameters to quantify underlying evolutionary relationships. Based on the proposed model, we formulate PPI network alignment as an optimization problem and present fast algorithms to solve this problem. Detailed experimental results from an implementation of the proposed framework show that our algorithm is able to discover conserved interaction patterns very effectively, in terms of both accuracies and computational cost.     

A binary matrix factorization algorithm for protein complex prediction

BACKGROUND: Identifying biologically relevant protein complexes from a large protein-protein interaction (PPI) network, is essential to understand the organization of biological systems. However, high-throughput experimental techniques that can produce a large amount of PPIs are known to yield non-negligible rates of false-positives and false-negatives, making the protein complexes difficult to be identified. RESULTS: We propose a binary matrix factorization (BMF) algorithm under the Bayesian Ying-Yang (BYY) harmony learning, to detect protein complexes by clustering the proteins which share similar interactions through factorizing the binary adjacent matrix of a PPI network. The proposed BYY-BMF algorithm automatically determines the cluster number while this number is pre-given for most existing BMF algorithms. Also, BYY-BMF's clustering results does not depend on any parameters or thresholds, unlike the Markov Cluster Algorithm (MCL) that relies on a so-called inflation parameter. On synthetic PPI networks, the predictions evaluated by the known annotated complexes indicate that BYY-BMF is more robust than MCL for most cases. On real PPI networks from the MIPS and DIP databases, BYY-BMF obtains a better balanced prediction accuracies than MCL and a spectral analysis method, while MCL has its own advantages, e.g., with good separation values.     

Filtering Gene Ontology semantic similarity for identifying protein complexes in large protein interaction networks

Background

Many biological processes recognize in particular the importance of protein complexes, and various computational approaches have been developed to identify complexes from protein-protein interaction (PPI) networks. However, high false-positive rate of PPIs leads to challenging identification.

Results

A protein semantic similarity measure is proposed in this study, based on the ontology structure of Gene Ontology (GO) terms and GO annotations to estimate the reliability of interactions in PPI networks. Interaction pairs with low GO semantic similarity are removed from the network as unreliable interactions. Then, a cluster-expanding algorithm is used to detect complexes with core-attachment structure on filtered network. Our method is applied to three different yeast PPI networks. The effectiveness of our method is examined on two benchmark complex datasets. Experimental results show that our method performed better than other state-of-the-art approaches in most evaluation metrics.

Conclusions

The method detects protein complexes from large scale PPI networks by filtering GO semantic similarity. Removing interactions with low GO similarity significantly improves the performance of complex identification. The expanding strategy is also effective to identify attachment proteins of complexes.

     

A method based on local density and random walks for complexes detection in protein interaction networks

In this paper, we present a method based on local density and random walks (LDRW) for core-attachment complexes detection in protein-protein interaction (PPI) networks whether they are weighted or not. Our LDRW method consists of two stages. Firstly, it finds all the protein-complex cores based on local density of subnetwork. Then it uses random walks with restarts for finding the attachment proteins of each detected core to form complexes. We evaluate the effectiveness of our method using two different yeast PPI networks and validate the biological significance of the predicted protein complexes using known complexes in the Munich Information Center for Protein Sequence (MIPS) and Gene Ontology (GO) databases. We also perform a comprehensive comparison between our method and other existing methods. The results show that our method can find more protein complexes with high biological significance and obtains a significant improvement. Furthermore, our method is able to identify biologically significant overlapped protein complexes.     

Protein complexes discovery based on protein-protein interaction data via a regularized sparse generative network model

Detecting protein complexes from protein interaction networks is one major task in the postgenome era. Previous developed computational algorithms identifying complexes mainly focus on graph partition or dense region finding. Most of these traditional algorithms cannot discover overlapping complexes which really exist in the protein-protein interaction (PPI) networks. Even if some density-based methods have been developed to identify overlapping complexes, they are not able to discover complexes that include peripheral proteins. In this study, motivated by recent successful application of generative network model to describe the generation process of PPI networks and to detect communities from social networks, we develop a regularized sparse generative network model (RSGNM), by adding another process that generates propensities using exponential distribution and incorporating Laplacian regularizer into an existing generative network model, for protein complexes identification. By assuming that the propensities are generated using exponential distribution, the estimators of propensities will be sparse, which not only has good biological interpretation but also helps to control the overlapping rate among detected complexes. And the Laplacian regularizer will lead to the estimators of propensities more smooth on interaction networks. Experimental results on three yeast PPI networks show that RSGNM outperforms six previous competing algorithms in terms of the quality of detected complexes. In addition, RSGNM is able to detect overlapping complexes and complexes including peripheral proteins simultaneously. These results give new insights about the importance of generative network models in protein complexes identification.     

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.     

Seed selection strategy in global network alignment without destroying the entire structures of functional modules

Background

Network alignment is one of the most common biological network comparison methods. Aligning protein-protein interaction (PPI) networks of different species is of great important to detect evolutionary conserved pathways or protein complexes across species through the identification of conserved interactions, and to improve our insight into biological systems. Global network alignment (GNA) problem is NP-complete, for which only heuristic methods have been proposed so far. Generally, the current GNA methods fall into global heuristic seed-and-extend approaches. These methods can not get the best overall consistent alignment between networks for the opinionated local seed. Furthermore These methods are lost in maximizing the number of aligned edges between two networks without considering the original structures of functional modules.

Methods

We present a novel seed selection strategy for global network alignment by constructing the pairs of hub nodes of networks to be aligned into multiple seeds. Beginning from every hub seed and using the membership similarity of nodes to quantify to what extent the nodes can participate in functional modules associated with current seed topologically we align the networks by modules. By this way we can maintain the functional modules are not damaged during the heuristic alignment process. And our method is efficient in resolving the fatal problem of most conventional algorithms that the initialization selected seeds have a direct influence on the alignment result. The similarity measures between network nodes (e.g., proteins) include sequence similarity, centrality similarity, and dynamic membership similarity and our algorithm can be called Multiple Hubs-based Alignment (MHA).

Results

When applying our seed selection strategy to several pairs of real PPI networks, it is observed that our method is working to strike a balance, extending the conserved interactions while maintaining the functional modules unchanged. In the case study, we assess the effectiveness of MHA on the alignment of the yeast and fly PPI networks. Our method outperforms state-of-the-art algorithms at detecting conserved functional modules and retrieves in particular 86% more conserved interactions than IsoRank.

Conclusions

We believe that our seed selection strategy will lead us to obtain more topologically and biologically similar alignment result. And it can be used as the reference and complement of other heuristic methods to seek more meaningful alignment results.

     

Discovering functional interaction patterns in protein-protein interaction networks

Background  

In recent years, a considerable amount of research effort has been directed to the analysis of biological networks with the availability of genome-scale networks of genes and/or proteins of an increasing number of organisms. A protein-protein interaction (PPI) network is a particular biological network which represents physical interactions between pairs of proteins of an organism. Major research on PPI networks has focused on understanding the topological organization of PPI networks, evolution of PPI networks and identification of conserved subnetworks across different species, discovery of modules of interaction, use of PPI networks for functional annotation of uncharacterized proteins, and improvement of the accuracy of currently available networks.     

Diffusion Model Based Spectral Clustering for Protein-Protein Interaction Networks

Background

A goal of systems biology is to analyze large-scale molecular networks including gene expressions and protein-protein interactions, revealing the relationships between network structures and their biological functions. Dividing a protein-protein interaction (PPI) network into naturally grouped parts is an essential way to investigate the relationship between topology of networks and their functions. However, clear modular decomposition is often hard due to the heterogeneous or scale-free properties of PPI networks.

Methodology/Principal Findings

To address this problem, we propose a diffusion model-based spectral clustering algorithm, which analytically solves the cluster structure of PPI networks as a problem of random walks in the diffusion process in them. To cope with the heterogeneity of the networks, the power factor is introduced to adjust the diffusion matrix by weighting the transition (adjacency) matrix according to a node degree matrix. This algorithm is named adjustable diffusion matrix-based spectral clustering (ADMSC). To demonstrate the feasibility of ADMSC, we apply it to decomposition of a yeast PPI network, identifying biologically significant clusters with approximately equal size. Compared with other established algorithms, ADMSC facilitates clear and fast decomposition of PPI networks.

Conclusions/Significance

ADMSC is proposed by introducing the power factor that adjusts the diffusion matrix to the heterogeneity of the PPI networks. ADMSC effectively partitions PPI networks into biologically significant clusters with almost equal sizes, while being very fast, robust and appealing simple.     

Gene gravity-like algorithm for disease gene prediction based on phenotype-specific network

Background

Polygenic diseases are usually caused by the dysfunction of multiple genes. Unravelling such disease genes is crucial to fully understand the genetic landscape of diseases on molecular level. With the advent of ‘omic’ data era, network-based methods have prominently boosted disease gene discovery. However, how to make better use of different types of data for the prediction of disease genes remains a challenge.

Results

In this study, we improved the performance of disease gene prediction by integrating the similarity of disease phenotype, biological function and network topology. First, for each phenotype, a phenotype-specific network was specially constructed by mapping phenotype similarity information of given phenotype onto the protein-protein interaction (PPI) network. Then, we developed a gene gravity-like algorithm, to score candidate genes based on not only topological similarity but also functional similarity. We tested the proposed network and algorithm by conducting leave-one-out and leave-10%-out cross validation and compared them with state-of-art algorithms. The results showed a preference to phenotype-specific network as well as gene gravity-like algorithm. At last, we tested the predicting capacity of proposed algorithms by test gene set derived from the DisGeNET database. Also, potential disease genes of three polygenic diseases, obesity, prostate cancer and lung cancer, were predicted by proposed methods. We found that the predicted disease genes are highly consistent with literature and database evidence.

Conclusions

The good performance of phenotype-specific networks indicates that phenotype similarity information has positive effect on the prediction of disease genes. The proposed gene gravity-like algorithm outperforms the algorithm of Random Walk with Restart (RWR), implicating its predicting capacity by combing topological similarity with functional similarity. Our work will give an insight to the discovery of disease genes by fusing multiple similarities of genes and diseases.

     

Ontology integration to identify protein complex in protein interaction networks

Background

Protein complexes can be identified from the protein interaction networks derived from experimental data sets. However, these analyses are challenging because of the presence of unreliable interactions and the complex connectivity of the network. The integration of protein-protein interactions with the data from other sources can be leveraged for improving the effectiveness of protein complexes detection algorithms.

Methods

We have developed novel semantic similarity method, which use Gene Ontology (GO) annotations to measure the reliability of protein-protein interactions. The protein interaction networks can be converted into a weighted graph representation by assigning the reliability values to each interaction as a weight. Following the approach of that of the previously proposed clustering algorithm IPCA which expands clusters starting from seeded vertices, we present a clustering algorithm OIIP based on the new weighted Protein-Protein interaction networks for identifying protein complexes.

Results

The algorithm OIIP is applied to the protein interaction network of Sacchromyces cerevisiae and identifies many well known complexes. Experimental results show that the algorithm OIIP has higher F-measure and accuracy compared to other competing approaches.

     

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.

     

Mining Dense Overlapping Subgraphs in weighted protein-protein interaction networks

Many methods have been proposed for mining protein complexes from a protein-protein interaction network; however, most of them focus on unweighted networks and cannot find overlapping protein complexes. Since one protein may serve different roles within different functional groups, mining overlapping protein complexes in a weighted protein-protein interaction network has attracted more and more attention recently. In this paper, we propose an effective method, called MDOS (Mining Dense Overlapping Subgraphs), for mining dense overlapping protein complexes (subgraphs) in a weighted protein-protein interaction network. The proposed method can integrate the information about known complexes into a weighted protein-protein interaction network to improve the mining results. The experiment results show that our method mines more known complexes and has higher sensitivity and accuracy than the CODENSE and MCL methods.     

Reconstructing Genome-Wide Protein–Protein Interaction Networks Using Multiple Strategies with Homologous Mapping

Background

One of the crucial steps toward understanding the biological functions of a cellular system is to investigate protein–protein interaction (PPI) networks. As an increasing number of reliable PPIs become available, there is a growing need for discovering PPIs to reconstruct PPI networks of interesting organisms. Some interolog-based methods and homologous PPI families have been proposed for predicting PPIs from the known PPIs of source organisms.

Results

Here, we propose a multiple-strategy scoring method to identify reliable PPIs for reconstructing the mouse PPI network from two well-known organisms: human and fly. We firstly identified the PPI candidates of target organisms based on homologous PPIs, sharing significant sequence similarities (joint E-value ≤ 1 × 10⁻⁴⁰), from source organisms using generalized interolog mapping. These PPI candidates were evaluated by our multiple-strategy scoring method, combining sequence similarities, normalized ranks, and conservation scores across multiple organisms. According to 106,825 PPI candidates in yeast derived from human and fly, our scoring method can achieve high prediction accuracy and outperform generalized interolog mapping. Experiment results show that our multiple-strategy score can avoid the influence of the protein family size and length to significantly improve PPI prediction accuracy and reflect the biological functions. In addition, the top-ranked and conserved PPIs are often orthologous/essential interactions and share the functional similarity. Based on these reliable predicted PPIs, we reconstructed a comprehensive mouse PPI network, which is a scale-free network and can reflect the biological functions and high connectivity of 292 KEGG modules, including 216 pathways and 76 structural complexes.

Conclusions

Experimental results show that our scoring method can improve the predicting accuracy based on the normalized rank and evolutionary conservation from multiple organisms. Our predicted PPIs share similar biological processes and cellular components, and the reconstructed genome-wide PPI network can reflect network topology and modularity. We believe that our method is useful for inferring reliable PPIs and reconstructing a comprehensive PPI network of an interesting organism.     

AlignNemo: a local network alignment method to integrate homology and topology

Local network alignment is an important component of the analysis of protein-protein interaction networks that may lead to the identification of evolutionary related complexes. We present AlignNemo, a new algorithm that, given the networks of two organisms, uncovers subnetworks of proteins that relate in biological function and topology of interactions. The discovered conserved subnetworks have a general topology and need not to correspond to specific interaction patterns, so that they more closely fit the models of functional complexes proposed in the literature. The algorithm is able to handle sparse interaction data with an expansion process that at each step explores the local topology of the networks beyond the proteins directly interacting with the current solution. To assess the performance of AlignNemo, we ran a series of benchmarks using statistical measures as well as biological knowledge. Based on reference datasets of protein complexes, AlignNemo shows better performance than other methods in terms of both precision and recall. We show our solutions to be biologically sound using the concept of semantic similarity applied to Gene Ontology vocabularies. The binaries of AlignNemo and supplementary details about the algorithms and the experiments are available at: sourceforge.net/p/alignnemo.