Identifying Protein Complexes by Combining Network Topology and Biological Characteristics

Advances in proteomic technologies combined with sophisticated computing and modeling methods have generated an unprecedented amount of high-throughput data for system-scale analysis. As a result, the study of protein-protein interaction (PPI) networks has garnered much attention in recent years. One of the most fundamental problems in studying PPI networks is to understand how their architecture originated and evolved to their current state. By investigating how proteins of different ages are connected in the yeast PPI networks, one can deduce their expansion procedure in evolution and how the ancient primitive network expanded and evolved. Studies have shown that proteins are often connected to other proteins of a similar age, suggesting a high degree of age preference between interacting proteins. Though several theories have been proposed to explain this phenomenon, none of them considered protein-clusters as a contributing factor. Here we first investigate the age-dependency of the proteins from the perspective of network motifs. Our analysis confirms that proteins of the same age groups tend to form interacting network motifs; furthermore, those proteins within motifs tend to be within protein complexes and the interactions among them largely contribute to the observed age preference in the yeast PPI networks. In light of these results, we describe a new modeling approach, based on "network motifs", whereby topologically connected protein clusters in the network are treated as single evolutionary units. Instead of modeling single proteins, our approach models the connections and evolutionary relationships of multiple related protein clusters or "network motifs" that are collectively integrated into an existing PPI network. Through simulation studies, we found that the "network motif" modeling approach can capture yeast PPI network properties better than if individual proteins were considered to be the simplest evolutionary units. Our approach provides a fresh perspective on modeling the evolution of yeast PPI networks, specifically that PPI networks may have a much higher age-dependency of interaction density than had been previously envisioned.

The protein-protein interaction (PPI) networks can be regarded as powerful platforms to elucidate the principle and mechanism of cellular organization. Uncovering protein complexes from PPI networks will lead to a better understanding of the science of biological function in cellular systems. In recent decades, numerous computational algorithms have been developed to identify protein complexes. However, the majority of them primarily concern the topological structure of PPI networks and lack of the consideration for the native organized structure among protein complexes. The PPI networks generated by high-throughput technology include a fraction of false protein interactions which make it difficult to identify protein complexes efficiently. To tackle these challenges, we propose a novel semi-supervised protein complex detection model based on non-negative matrix tri-factorization, which not only considers topological structure of a PPI network but also makes full use of available high quality known protein pairs with must-link constraints. We propose non-overlapping (NSSNMTF) and overlapping (OSSNMTF) protein complex detection algorithms to identify the significant protein complexes with clear module structures from PPI networks. In addition, the proposed two protein complex detection algorithms outperform a diverse range of state-of-the-art protein complex identification algorithms on both synthetic networks and human related PPI networks.

Identifying overlapping protein complexes in protein-protein interaction (PPI) networks can provide insight into cellular functional organization and thus elucidate underlying cellular mechanisms. Recently, various algorithms for protein complexes detection have been developed for PPI networks. However, majority of algorithms primarily depend on network topological feature and/or gene expression profile, failing to consider the inherent biological meanings between protein pairs. In this paper, we propose a novel method to detect protein complexes using pseudo-clique extension based on fuzzy relation (PCE-FR). Our algorithm operates in three stages: it first forms the nonoverlapping protein substructure based on fuzzy relation and then expands each substructure by adding neighbor proteins to maximize the cohesive score. Finally, highly overlapped candidate protein complexes are merged to form the final protein complex set. Particularly, our algorithm employs the biological significance hidden in protein pairs to construct edge weight for protein interaction networks. The experiment results show that our method can not only outperform classical algorithms such as CFinder, ClusterONE, CMC, RRW, HC-PIN, and ProRank +, but also achieve ideal overall performance in most of the yeast PPI datasets in terms of composite score consisting of precision, accuracy, and separation. We further apply our method to a human PPI network from the HPRD dataset and demonstrate it is very effective in detecting protein complexes compared to other algorithms.

A network of modular protein complexes inside a cell coordinates many biological processes and is known as protein-protein interaction (PPI) network. A PPI network can be modeled as a graph, in which edges represent interactions among proteins, and sub graphs represent protein complexes. Previous methods for protein complex mining from PPI network mainly focused on few topological features like density and degree statistics based on the assumption that proteins inside a complex are highly interactive with each other and thus form dense subgraphs. While this assumption is true for some complexes, it doesn’t hold for many others. The important biological information within the protein amino acid sequences, which estimates the interacting property among two proteins for performing a specific biological function is not considered in most of the previous studies. There is a need for algorithms that consider both topological and biological features for correctly identifying protein complexes having varying topological structures and biological patterns inside a PPI network. In this paper, we present an algorithm for detecting protein complexes from interaction graphs. By using graph topological patterns and biological properties as features, we model each complex sub graph by decision tree learners. We use a training set of known complexes to construct decision trees in depth first and BEST FIRST manner using divide and conquer strategy. Splitting criterion, such as information and Gini gain are used in tree expansion process. Training set is divided into subsets and each subset is represented as a branch of tree. Pruning techniques are used to reduce the size of tree. We applied our method to protein interaction data in yeast on two benchmark data sets, i.e., MIPS and CYC2008. According to our results, decision trees achieved a considerable improvement over clique-based algorithms in terms of its ability to recover known complexes by using integrated biological and topological properties.

The problem of identifying protein complexes in Protein-Protein Interaction (PPI) networks is usually formulated as the problem of identifying dense regions in such networks. In this paper, we present a novel approach, called TBPCI, to identify protein complexes based instead on the concept of a measure of boundedness. Such a measure is defined as an objective function of a Jaccard Index-based connectedness measure which takes into consideration how much two proteins within a network are connected to each other, and an association measure which takes into consideration how much two connecting proteins are associated based on their attributes found in the Gene Ontology database. Based on the above two measures, the objective function is derived to capture how strong the proteins can be considered as bounded together and the objective value is therefore referred as the aggregated degree of boundedness. To identify protein complexes, TBPCI computes the degree of boundedness between all possible pairwise proteins. Then, TBPCI uses a Breadth-First-Search method to determine whether a protein-pair should be incorporated into the same complex. TBPCI has been tested with several real data sets and the experimental results show it is an effective approach for identifying protein complexes in PPI networks.

Protein-protein interaction (PPI) networks provide a well-established framework for elucidating structural properties. In contrast, much greater effort is required to identify useful and/or hidden information using the approach because of the complexity of the networks. Accordingly, an appropriate methodology that allows characterization of a simple, but core, sub-network of a complex network would be a potentially valuable alternative approach. Here, we employed k-core decomposition as a useful tool for obtaining core sub-networks from the complex PPI network in yeast. To apply a k-core value to the complex yeast PPI network, we constructed cytoplasmic and nuclear core sub-networks. We measured the lethality of proteins and the ratio of hub to non-hub core sub-network proteins at each k-core value step. With increasing k-core value, the values of the two parameters gradually increased. Application of 6- and 7-core values to cytoplasmic and nuclear PPI networks yielded modular, structured core sub-networks that were functionally specialized. We also elucidated a false hub: a structural hub exhibiting no functional roles or lethal properties in the network. By employing k-core decomposition to cytoplasmic and nuclear PPI networks in yeast, we obtained useful and/or hidden information during the core sub-network construction process, indicating that k-core decomposition is a useful tool for structural and informational network studies. Notably, we found false hub proteins that might provide insight into protein networks and clues to understanding network evolution.

Biological functions of a cell are typically carried out through protein complexes. The detection of protein complexes is therefore of great significance for understanding the cellular organizations and protein functions. In the past decades, many computational methods have been proposed to detect protein complexes. However, most of the existing methods just search the local topological information to mine dense subgraphs as protein complexes, ignoring the global topological information. To tackle this issue, we propose the DPCMNE method to detect protein complexes via multi-level network embedding. It can preserve both the local and global topological information of biological networks. First, DPCMNE employs a hierarchical compressing strategy to recursively compress the input protein-protein interaction (PPI) network into multi-level smaller PPI networks. Then, a network embedding method is applied on these smaller PPI networks to learn protein embeddings of different levels of granularity. The embeddings learned from all the compressed PPI networks are concatenated to represent the final protein embeddings of the original input PPI network. Finally, a core-attachment based strategy is adopted to detect protein complexes in the weighted PPI network constructed by the pairwise similarity of protein embeddings. To assess the efficiency of our proposed method, DPCMNE is compared with other eight clustering algorithms on two yeast datasets. The experimental results show that the performance of DPCMNE outperforms those state-of-the-art complex detection methods in terms of F1 and F1+Acc. Furthermore, the results of functional enrichment analysis indicate that protein complexes detected by DPCMNE are more biologically significant in terms of P-score.

Protein Complex Detection in PPI Network by Identifying Mutually Exclusive Protein-protein Interactions

Protein complexes play significant roles in cellular processes. Identifying protein complexes from protein-protein interaction (PPI) networks is an effective strategy to understand biological processes and cellular functions. A number of methods have recently been proposed to detect protein complexes. However, most of methods predict protein complexes from static PPI networks, and usually overlook the inherent dynamics and topological properties of protein complexes. In this paper, we proposed a novel method, called NABCAM (Neighbor Affinity-Based Core-Attachment Method), to identify protein complexes from dynamic PPI networks. Firstly, the centrality score of every protein is calculated. The proteins with the highest centrality scores are regarded as the seed proteins. Secondly, the seed proteins are expanded to complex cores by calculating the similarity values between the seed proteins and their neighboring proteins. Thirdly, the attachments are appended to their corresponding protein complex cores by comparing the affinity among neighbors inside the core, against that outside the core. Finally, filtering processes are carried out to obtain the final clustering result. The result in the DIP database shows that the NABCAM algorithm can predict protein complexes effectively in comparison with other state-of-the-art methods. Moreover, many protein complexes predicted by our method are biologically significant.

Detecting protein complexes is one of the keys to understanding cellular organization and processes principles. With high-throughput experiments and computing science development, it has become possible to detect protein complexes by computational methods. However, most computational methods are based on either unsupervised learning or supervised learning. Unsupervised learning-based methods do not need training datasets, but they can only detect one or several topological protein complexes. Supervised learning-based methods can detect protein complexes with different topological structures. However, they are usually based on a type of training model, and the generalization of a single model is poor. Therefore, we propose an Ensemble Learning Framework for Detecting Protein Complexes (ELF-DPC) within protein-protein interaction (PPI) networks to address these challenges. The ELF-DPC first constructs the weighted PPI network by combining topological and biological information. Second, it mines protein complex cores using the protein complex core mining strategy we designed. Third, it obtains an ensemble learning model by integrating structural modularity and a trained voting regressor model. Finally, it extends the protein complex cores and forms protein complexes by a graph heuristic search strategy. The experimental results demonstrate that ELF-DPC performs better than the twelve state-of-the-art approaches. Moreover, functional enrichment analysis illustrated that ELF-DPC could detect biologically meaningful protein complexes. The code/dataset is available for free download from https://github.com/RongquanWang/ELF-DPC.

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

Detecting protein complexes from available protein-protein interaction (PPI) data will help to deeply understand the mechanism of the biological activities. In recent years, various computational methods have been developed for identifying protein complexes from PPI networks. Almost all the basic computational methods mainly depend on the association of topological analysis of PPI networks. However, most of them fail to satisfactorily capture the global and local topological structures of the PPI networks, as well as the diversity of connectivity patterns between individual nodes at the same time. To solve this problem, in this work we propose a node embedding based alias sampling extension method to detect protein complexes. More specifically, for a given set of seed nodes, it first uses the alias sampling strategy based on protein node embedding similarities to select potential addable nodes. Then it makes use of a new conductance measure, which could better quantify the likelihood of a subgraph being a protein complex, to decide whether to extend the current candidate subgraph in order to find protein complexes. Evaluated on six real yeast PPI networks, our method outperforms state-of-the-art methods in detecting protein complexes. Furthermore, the experimental results demonstrate the protein complexes predicted by our method have higher biological significance.

Protein complexes are aggregates of protein molecules that play important roles in biological processes. Detecting protein complexes from protein-protein interaction (PPI) networks is one of the most challenging problems in computational biology, and many computational methods have been developed to solve this problem. Generally, these methods yield high false positive rates. In this article, a semantic similarity measure between proteins, based on Gene Ontology (GO) structure, is applied to weigh PPI networks. Consequently, one of the well-known methods, COACH, has been improved to be compatible with weighted PPI networks for protein complex detection. The new method, WCOACH, is compared to the COACH, ClusterOne, IPCA, CORE, OH-PIN, HC-PIN and MCODE methods on several PPI networks such as DIP, Krogan, Gavin 2002 and MIPS. WCOACH can be applied as a fast and high-performance algorithm to predict protein complexes in weighted PPI networks. All data and programs are freely available at http://bioinformatics.aut.ac.ir/wcoach.

Protein complex detection is an important issue in the field of system biology, which is crucial to understanding the cellular organization and inferring protein functions. In recent years, various computational methods have been proposed to detect protein complexes from protein-protein interaction (PPI) networks. Unfortunately, most of these methods only use the local information of PPI networks and treat protein complexes as dense subgraphs, ignoring the global topology information of PPI networks. To address these limitations, we propose a new method, named OPCMTS, to detect overlapping protein complexes by simultaneously considering the local topological information and global topological information of PPI network. First, a local similarity matrix is constructed via calculating the Jaccard coefficients between proteins in the original PPI network. Then, we adopt a hierarchical compressing strategy to get multiple levels of gradually compressed smaller networks from the original PPI network and apply a network embedding model to learn protein embeddings from the compressed networks at multiple levels. The protein embeddings from these networks are concatenated and a dimensionality reduction strategy is adopted to remove the redundancy of the concatenated embeddings to generate the final embeddings. Further, a global similarity matrix is constructed by calculating the cosine similarity of the final embeddings. Finally, a core-attachment strategy is used to detect overlapping protein complexes based on the local and global similarity matrices. The experimental results prove that the proposed OPCMTS method outperforms other five state-of-the-art methods in terms of F-measure on two yeast datasets.

BackgroundAccurate determination of protein complexes has become a key task of system biology for revealing cellular organization and function. Up to now, the protein complex prediction methods are mostly focused on static protein protein interaction (PPI) networks. However, cellular systems are highly dynamic and responsive to cues from the environment. The shift from static PPI networks to dynamic PPI networks is essential to accurately predict protein complex.ResultsThe gene expression data contains crucial dynamic information of proteins and PPIs, along with high-throughput experimental PPI data, are valuable for protein complex prediction. Firstly, we exploit gene expression data to calculate the active time point and the active probability of each protein and PPI. The dynamic active information is integrated into high-throughput PPI data to construct dynamic PPI networks. Secondly, a novel method for predicting protein complexes from the dynamic PPI networks is proposed based on core-attachment structural feature. Our method can effectively exploit not only the dynamic active information but also the topology structure information based on the dynamic PPI networks.ConclusionsWe construct four dynamic PPI networks, and accurately predict many well-characterized protein complexes. The experimental results show that (i) the dynamic active information significantly improves the performance of protein complex prediction; (ii) our method can effectively make good use of both the dynamic active information and the topology structure information of dynamic PPI networks to achieve state-of-the-art protein complex prediction capabilities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1101-y) contains supplementary material, which is available to authorized users.