Overlapping Protein Complexes Research Articles

Overlapping complexes detection within protein interaction networks using improved genetic algorithm

BackgroundThe protein complexes detection has an important role in analyzing biological processes and understanding life at the cellular level. Although many complex detection algorithms have been proposed by employing specific topological attributes of protein interaction networks, most of them focus on detecting separated protein complexes, where each protein can belong to only one complex. Generally, many protein interaction networks have many complexes or modules that are often overlapped with each other. Developing overlapping protein complex detection algorithm thus becomes necessary. MethodsIn this respect, this paper proposes a new overlapping detection algorithm based on GA (Genetic Algorithm) to discover overlapping protein complexes. The proposed algorithm is supplied with a new local search operator based on gene ontology annotations in order to direct the search process towards discovering overlapping protein complexes that are hyper-connected and biologically related. The proposed algorithm is assessed on two gold standard and real-world datasets. ResultsThe result attained shows that the proposed algorithm can detect important overlapping protein complexes, and presents more accurate results compared to the state-of-the-art overlapping protein complexes detection algorithms. ConclusionsThe superior performance of the proposed algorithm compared with other counterpart algorithms is attributed to the fact that the proposed algorithm is a population based stochastic search algorithm which efficiently explored the search landscape to capture dense overlapping subgraphs by employing the topological properties of network, and then enhancing the obtained solution by investing gene ontology information in developing a new local search operator inside the GA framework.

Identifying Protein Complexes From Protein-Protein Interaction Networks Based on Fuzzy Clustering and GO Semantic Information.

Protein complexes are of great significance to provide valuable insights into the mechanisms of biological processes of proteins. A variety of computational algorithms have thus been proposed to identify protein complexes in a protein-protein interaction network. However, few of them can perform their tasks by taking into account both network topology and protein attribute information in a unified fuzzy-based clustering framework. Since proteins in the same complex are similar in terms of their attribute information and the consideration of fuzzy clustering can also make it possible for us to identify overlapping complexes, we target to propose such a novel fuzzy-based clustering framework, namely FCAN-PCI, for an improved identification accuracy. To do so, the semantic similarity between the attribute information of proteins is calculated and we then integrate it into a well-established fuzzy clustering model together with the network topology. After that, a momentum method is adopted to accelerate the clustering procedure. FCAN-PCI finally applies a heuristical search strategy to identify overlapping protein complexes. A series of extensive experiments have been conducted to evaluate the performance of FCAN-PCI by comparing it with state-of-the-art identification algorithms and the results demonstrate the promising performance of FCAN-PCI.

An Effective Link-Based Clustering Algorithm for Detecting Overlapping Protein Complexes in Protein-Protein Interaction Networks

Protein complexes are one most important kind of functional modules for biological processes in cells. In this regard, their detection is vital for understanding the principle of cell organization and function. A variety of clustering algorithms have been developed to detect protein complexes from protein-protein interaction (PPI) networks. However, most of them are based on a certain clustering criterion. Given the fact that proteins should interact with each other rather than act independently, we reason that clustering upon interactions can better characterize protein complexes than upon proteins, thus improving the detection accuracy. To this end, a link-based clustering algorithm has been proposed in this paper to effectively detect overlapping protein complexes. It first measures the similarity between pairwise interactions from the perspectives of network topology and Gene Ontology. The problem of protein complex detection is then formulated as an optimization problem of link-based clustering, which is resolved by the proposed algorithm. This proposed algorithm explores the intrinsic correlation between protein complexes and interactions for detecting functionally significant protein complexes. Experimental results on five independent PPI datasets collected from the species of yeast and human demonstrate that compared with state-of-the-art algorithms, the proposed algorithm has significantly improved the detection accuracy for protein complexes.

SETS: A Seed-Dense-Expanding Model-Based Topological Structure for the Prediction of Overlapping Protein Complexes

Defining protein complexes by analysing the protein–protein interaction (PPI) networks is a crucial task in understanding the principles of a biological cell. In the last few decades, researchers have proposed numerous methods to explore the topological structure of a PPI network to detect dense protein complexes. In this paper, the overlapping protein complexes with different densities are predicted within an acceptable execution time using seed expanding model and topological structure of the PPI network (SETS). SETS depend on the relation between the seed and its neighbours. The algorithm was compared with six algorithms on six datasets: five for yeast and one for human. The results showed that SETS outperformed other algorithms in terms of F-measure, coverage rate and the number of complexes that have high similarity with real complexes.

HiSCF: leveraging higher-order structures for clustering analysis in biological networks.

Clustering analysis in a biological network is to group biological entities into functional modules, thus providing valuable insight into the understanding of complex biological systems. Existing clustering techniques make use of lower-order connectivity patterns at the level of individual biological entities and their connections, but few of them can take into account of higher-order connectivity patterns at the level of small network motifs. Here, we present a novel clustering framework, namely HiSCF, to identify functional modules based on the higher-order structure information available in a biological network. Taking advantage of higher-order Markov stochastic process, HiSCF is able to perform the clustering analysis by exploiting a variety of network motifs. When compared with several state-of-the-art clustering models, HiSCF yields the best performance for two practical clustering applications, i.e. protein complex identification and gene co-expression module detection, in terms of accuracy. The promising performance of HiSCF demonstrates that the consideration of higher-order network motifs gains new insight into the analysis of biological networks, such as the identification of overlapping protein complexes and the inference of new signaling pathways, and also reveals the rich higher-order organizational structures presented in biological networks. HiSCF is available at https://github.com/allenv5/HiSCF. Supplementary data are available at Bioinformatics online.

A novel graph clustering method with a greedy heuristic search algorithm for mining protein complexes from dynamic and static PPI networks

Discovering protein complexes from protein-protein interaction (PPI) networks is one of the primary tasks in bioinformatics. However, most of the state-of-the-art methods still face some challenges, such as the inability to discover overlapping protein complexes, failure to consider the inherent structure of real protein complexes, and non-utilization of biological information. Based on the above mentioned aspects, we present a novel graph clustering method with a greedy heuristic search algorithm for mining protein complexes using a new clustering model in dynamic and static weighted PPI networks (named MPC-C). First, MPC-C constructed dynamic and static weighted PPI networks by combining biological and topological information. Second, initial clusters were obtained using core and multifunctional proteins, following which we proposed a greedy heuristic search algorithm to expand each initial cluster and form candidate protein complexes in dynamic and static weighted PPI networks. Finally, unreliable and highly overlapping protein complexes were discarded. To demonstrate the performance of MPC-C, we tested this method on five PPI networks and compared it with nine other effective methods. The experimental results indicate that MPC-C outperformed the other state-of-the-art methods with respect to various computational and biologically relevant metrics.

Detecting overlapping protein complexes in weighted PPI network based on overlay network chain in quotient space

BackgroundProtein complexes are the cornerstones of many biological processes and gather them to form various types of molecular machinery that perform a vast array of biological functions. In fact, a protein may belong to multiple protein complexes. Most existing protein complex detection algorithms cannot reflect overlapping protein complexes. To solve this problem, a novel overlapping protein complexes identification algorithm is proposed.ResultsIn this paper, a new clustering algorithm based on overlay network chain in quotient space, marked as ONCQS, was proposed to detect overlapping protein complexes in weighted PPI networks. In the quotient space, a multilevel overlay network is constructed by using the maximal complete subgraph to mine overlapping protein complexes. The GO annotation data is used to weight the PPI network. According to the compatibility relation, the overlay network chain in quotient space was calculated. The protein complexes are contained in the last level of the overlay network. The experiments were carried out on four PPI databases, and compared ONCQS with five other state-of-the-art methods in the identification of protein complexes.ConclusionsWe have applied ONCQS to four PPI databases DIP, Gavin, Krogan and MIPS, the results show that it is superior to other five existing algorithms MCODE, MCL, CORE, ClusterONE and COACH in detecting overlapping protein complexes.

Predicting overlapping protein complexes based on core-attachment and a local modularity structure

BackgroundIn recent decades, detecting protein complexes (PCs) from protein-protein interaction networks (PPINs) has been an active area of research. There are a large number of excellent graph clustering methods that work very well for identifying PCs. However, most of existing methods usually overlook the inherent core-attachment organization of PCs. Therefore, these methods have three major limitations we should concern. Firstly, many methods have ignored the importance of selecting seed, especially without considering the impact of overlapping nodes as seed nodes. Thus, there may be false predictions. Secondly, PCs are generally supposed to be dense subgraphs. However, the subgraphs with high local modularity structure usually correspond to PCs. Thirdly, a number of available methods lack handling noise mechanism, and miss some peripheral proteins. In summary, all these challenging issues are very important for predicting more biological overlapping PCs.ResultsIn this paper, to overcome these weaknesses, we propose a clustering method by core-attachment and local modularity structure, named CALM, to detect overlapping PCs from weighted PPINs with noises. Firstly, we identify overlapping nodes and seed nodes. Secondly, for a node, we calculate the support function between a node and a cluster. In CALM, a cluster which initially consists of only a seed node, is extended by adding its direct neighboring nodes recursively according to the support function, until this cluster forms a locally optimal modularity subgraph. Thirdly, we repeat this process for the remaining seed nodes. Finally, merging and removing procedures are carried out to obtain final predicted clusters. The experimental results show that CALM outperforms other classical methods, and achieves ideal overall performance. Furthermore, CALM can match more complexes with a higher accuracy and provide a better one-to-one mapping with reference complexes in all test datasets. Additionally, CALM is robust against the high rate of noise PPIN.ConclusionsBy considering core-attachment and local modularity structure, CALM could detect PCs much more effectively than some representative methods. In short, CALM could potentially identify previous undiscovered overlapping PCs with various density and high modularity.

Identification of overlapping protein complexes by fuzzy K-medoids clustering algorithm in yeast protein-protein interaction networks

Identification of overlapping protein complexes by fuzzy K-medoids clustering algorithm in yeast protein-protein interaction networks

RocSampler: regularizing overlapping protein complexes in protein-protein interaction networks

BackgroundIn recent years, protein-protein interaction (PPI) networks have been well recognized as important resources to elucidate various biological processes and cellular mechanisms. In this paper, we address the problem of predicting protein complexes from a PPI network. This problem has two difficulties. One is related to small complexes, which contains two or three components. It is relatively difficult to identify them due to their simpler internal structure, but unfortunately complexes of such sizes are dominant in major protein complex databases, such as CYC2008. Another difficulty is how to model overlaps between predicted complexes, that is, how to evaluate different predicted complexes sharing common proteins because CYC2008 and other databases include such protein complexes. Thus, it is critical how to model overlaps between predicted complexes to identify them simultaneously.ResultsIn this paper, we propose a sampling-based protein complex prediction method, RocSampler (Regularizing Overlapping Complexes), which exploits, as part of the whole scoring function, a regularization term for the overlaps of predicted complexes and that for the distribution of sizes of predicted complexes. We have implemented RocSampler in MATLAB and its executable file for Windows is available at the site, http://imi.kyushu-u.ac.jp/~om/software/RocSampler/.ConclusionsWe have applied RocSampler to five yeast PPI networks and shown that it is superior to other existing methods. This implies that the design of scoring functions including regularization terms is an effective approach for protein complex prediction.

Protein Complexes Prediction Method Based on Core-Attachment Structure and Functional Annotations.

Recent advances in high-throughput laboratory techniques captured large-scale protein–protein interaction (PPI) data, making it possible to create a detailed map of protein interaction networks, and thus enable us to detect protein complexes from these PPI networks. However, most of the current state-of-the-art studies still have some problems, for instance, incapability of identifying overlapping clusters, without considering the inherent organization within protein complexes, and overlooking the biological meaning of complexes. Therefore, we present a novel overlapping protein complexes prediction method based on core–attachment structure and function annotations (CFOCM), which performs in two stages: first, it detects protein complex cores with the maximum value of our defined cluster closeness function, in which the proteins are also closely related to at least one common function. Then it appends attach proteins into these detected cores to form the returned complexes. For performance evaluation, CFOCM and six classical methods have been used to identify protein complexes on three different yeast PPI networks, and three sets of real complexes including the Munich Information Center for Protein Sequences (MIPS), the Saccharomyces Genome Database (SGD) and the Catalogues of Yeast protein Complexes (CYC2008) are selected as benchmark sets, and the results show that CFOCM is indeed effective and robust for achieving the highest F-measure values in all tests.

Finding low-conductance sets with dense interactions (FLCD) for better protein complex prediction

BackgroundIntuitively, proteins in the same protein complexes should highly interact with each other but rarely interact with the other proteins in protein-protein interaction (PPI) networks. Surprisingly, many existing computational algorithms do not directly detect protein complexes based on both of these topological properties. Most of them, depending on mathematical definitions of either “modularity” or “conductance”, have their own limitations: Modularity has the inherent resolution problem ignoring small protein complexes; and conductance characterizes the separability of complexes but fails to capture the interaction density within complexes.ResultsIn this paper, we propose a two-step algorithm FLCD (Finding Low-Conductance sets with Dense interactions) to predict overlapping protein complexes with the desired topological structure, which is densely connected inside and well separated from the rest of the networks. First, FLCD detects well-separated subnetworks based on approximating a potential low-conductance set through a personalized PageRank vector from a protein and then solving a mixed integer programming (MIP) problem to find the minimum-conductance set within the identified low-conductance set. At the second step, the densely connected parts in those subnetworks are discovered as the protein complexes by solving another MIP problem that aims to find the dense subnetwork in the minimum-conductance set.ConclusionExperiments on four large-scale yeast PPI networks from different public databases demonstrate that the complexes predicted by FLCD have better correspondence with the yeast protein complex gold standards than other three state-of-the-art algorithms (ClusterONE, LinkComm, and SR-MCL). Additionally, results of FLCD show higher biological relevance with respect to Gene Ontology (GO) terms by GO enrichment analysis.

PCE-FR: A Novel Method for Identifying Overlapping Protein Complexes in Weighted Protein-Protein Interaction Networks Using Pseudo-Clique Extension Based on Fuzzy Relation.

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.

Predicting overlapping protein complexes from weighted protein interaction graphs by gradually expanding dense neighborhoods.

Proteins are vital biological molecules driving many fundamental cellular processes. They rarely act alone, but form interacting groups called protein complexes. The study of protein complexes is a key goal in systems biology. Recently, large protein-protein interaction (PPI) datasets have been published and a plethora of computational methods that provide new ideas for the prediction of protein complexes have been implemented. However, most of the methods suffer from two major limitations: First, they do not account for proteins participating in multiple functions and second, they are unable to handle weighted PPI graphs. Moreover, the problem remains open as existing algorithms and tools are insufficient in terms of predictive metrics. In the present paper, we propose gradually expanding neighborhoods with adjustment (GENA), a new algorithm that gradually expands neighborhoods in a graph starting from highly informative "seed" nodes. GENA considers proteins as multifunctional molecules allowing them to participate in more than one protein complex. In addition, GENA accepts weighted PPI graphs by using a weighted evaluation function for each cluster. In experiments with datasets from Saccharomyces cerevisiae and human, GENA outperformed Markov clustering, restricted neighborhood search and clustering with overlapping neighborhood expansion, three state-of-the-art methods for computationally predicting protein complexes. Seven PPI networks and seven evaluation datasets were used in total. GENA outperformed existing methods in 16 out of 18 experiments achieving an average improvement of 5.5% when the maximum matching ratio metric was used. Our method was able to discover functionally homogeneous protein clusters and uncover important network modules in a Parkinson expression dataset. When used on the human networks, around 47% of the detected clusters were enriched in gene ontology (GO) terms with depth higher than five in the GO hierarchy. In the present manuscript, we introduce a new method for the computational prediction of protein complexes by making the realistic assumption that proteins participate in multiple protein complexes and cellular functions. Our method can detect accurate and functionally homogeneous clusters.

A two-layer integration framework for protein complex detection.

BackgroundProtein complexes carry out nearly all signaling and functional processes within cells. The study of protein complexes is an effective strategy to analyze cellular functions and biological processes. With the increasing availability of proteomics data, various computational methods have recently been developed to predict protein complexes. However, different computational methods are based on their own assumptions and designed to work on different data sources, and various biological screening methods have their unique experiment conditions, and are often different in scale and noise level. Therefore, a single computational method on a specific data source is generally not able to generate comprehensive and reliable prediction results.ResultsIn this paper, we develop a novel Two-layer INtegrative Complex Detection (TINCD) model to detect protein complexes, leveraging the information from both clustering results and raw data sources. In particular, we first integrate various clustering results to construct consensus matrices for proteins to measure their overall co-complex propensity. Second, we combine these consensus matrices with the co-complex score matrix derived from Tandem Affinity Purification/Mass Spectrometry (TAP) data and obtain an integrated co-complex similarity network via an unsupervised metric fusion method. Finally, a novel graph regularized doubly stochastic matrix decomposition model is proposed to detect overlapping protein complexes from the integrated similarity network.ConclusionsExtensive experimental results demonstrate that TINCD performs much better than 21 state-of-the-art complex detection techniques, including ensemble clustering and data integration techniques.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-0939-3) contains supplementary material, which is available to authorized users.

Detection of overlapping protein complexes in gene expression, phenotype and pathways of Saccharomyces cerevisiae using Prorank based Fuzzy algorithm

Proteins show their functional activity by interacting with other proteins and forms protein complexes since it is playing an important role in cellular organization and function. To understand the higher order protein organization, overlapping is an important step towards unveiling functional and evolutionary mechanisms behind biological networks. Most of the clustering algorithms do not consider the weighted as well as overlapping complexes. In this research, Prorank based Fuzzy algorithm has been proposed to find the overlapping protein complexes. The Fuzzy detection algorithm is incorporated in the Prorank algorithm after ranking step to find the overlapping community. The proposed algorithm executes in an iterative manner to compute the probability of robust clusters. The proposed and the existing algorithms were tested on different datasets such as PPI-D1, PPI-D2, Collins, DIP, Krogan Core and Krogan-Extended, gene expression such as GSE7645, GSE22269, GSE26923, pathways such as Meiosis, MAPK, Cell Cycle, phenotypes such as Yeast Heterogeneous and Yeast Homogeneous datasets. The experimental results show that the proposed algorithm predicts protein complexes with better accuracy compared to other state of art algorithms.

Identification of Overlapping Protein Complexes Using Structural and Functional Information of PPI Network

An identification algorithm of overlapping protein complexes is put forward by simultaneously considering the topological structural and biological functional information of Protein-protein interaction (PPI) network. Main works include: constructing the edge weight of weighted PPI network on the basis of structural and functional information of PPI network to more accurately describe the correlation between protein vertices; improving the Newman algorithm to make it applicable to weighted PPI network and thus to identify overlapping protein complexes; and providing the denoising criteria based on the structural and function information of PPI network: connections which have no contribution to the high aggregation of PPI network or which are among proteins of independent functions are judged to be false positive connections. The experimental results on the dataset of saccharomyces cerevisiae PPI network show that the proposed algorithm has higher identification accuracy and matching rate when compared with the current representative identification algorithms of protein complexes.

A density-based clustering approach for identifying overlapping protein complexes with functional preferences

BackgroundIdentifying protein complexes is an essential task for understanding the mechanisms of proteins in cells. Many computational approaches have thus been developed to identify protein complexes in protein-protein interaction (PPI) networks. Regarding the information that can be adopted by computational approaches to identify protein complexes, in addition to the graph topology of PPI network, the consideration of functional information of proteins has been becoming popular recently. Relevant approaches perform their tasks by relying on the idea that proteins in the same protein complex may be associated with similar functional information. However, we note from our previous researches that for most protein complexes their proteins are only similar in specific subsets of categories of functional information instead of the entire set. Hence, if the preference of each functional category can also be taken into account when identifying protein complexes, the accuracy will be improved.ResultsTo implement the idea, we first introduce a preference vector for each of proteins to quantitatively indicate the preference of each functional category when deciding the protein complex this protein belongs to. Integrating functional preferences of proteins and the graph topology of PPI network, we formulate the problem of identifying protein complexes into a constrained optimization problem, and we propose the approach DCAFP to address it. For performance evaluation, we have conducted extensive experiments with several PPI networks from the species of Saccharomyces cerevisiae and Human and also compared DCAFP with state-of-the-art approaches in the identification of protein complexes. The experimental results show that considering the integration of functional preferences and dense structures improved the performance of identifying protein complexes, as DCAFP outperformed the other approaches for most of PPI networks based on the assessments of independent measures of f-measure, Accuracy and Maximum Matching Rate. Furthermore, the function enrichment experiments indicated that DCAFP identified more protein complexes with functional significance when compared with approaches, such as PCIA, that also utilize the functional information.ConclusionsAccording to the promising performance of DCAFP, the integration of functional preferences and dense structures has made it possible to identify protein complexes more accurately and significantly.

ReSAPP: predicting overlapping protein complexes by merging multiple-sampled partitions of proteins.

Many proteins are known to perform their own functions when they form particular groups of proteins, called protein complexes. With the advent of large-scale protein-protein interaction (PPI) studies, it has been a challenging problem in systems biology to predict protein complexes from PPIs. In this paper, we propose a novel method, called Repeated Simulated Annealing of Partitions of Proteins (ReSAPP), which predicts protein complexes from weighted PPIs. ReSAPP, in the first stage, generates multiple (possibly different) partitions of all proteins of given PPIs by repeatedly applying a simulated annealing based optimization algorithm to the PPIs. In the second stage, all different clusters of size two or more in those multiple partitions are merged into a collection of those clusters, which are outputted as predicted protein complexes. In performance comparison of ReSAPP with our previous algorithm, PPSampler2, as well as other various tools, MCL, MCODE, DPClus, CMC, COACH, RRW, NWE, and PPSampler1, ReSAPP is shown to outperform the other methods. Furthermore, the value of F-measure of ReSAPP is higher than that of the variant of ReSAPP without merging partitions. Thus, we empirically conclude that the combination of sampling multiple partitions and merging them is effective to predict protein complexes.

Detecting temporal protein complexes from dynamic protein-protein interaction networks.

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