IOPTICS-GSO for identifying protein complexes from dynamic PPI networks

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.

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.

Identifying protein complexes in protein-protein interaction (ppi) networks is often handled as a community detection problem, with algorithms generally relying exclusively on the network topology for discovering a solution. The advancement of experimental techniques on ppi has motivated the generation of many Gene Ontology (go) databases. Incorporating the functionality extracted from go with the topological properties from the underlying ppi network yield a novel approach to identify protein complexes. Additionally, most of the existing algorithms use global measures that operate on the entire network to identify communities. The result of using global metrics are large communities that are often not correlated with the functionality of the proteins. Moreover, ppi network analysis shows that most of the biological functions possibly lie between local neighbours in ppi networks, which are not identifiable with global metrics. In this paper, we propose a local community detection algorithm, (lcda-go), that uniquely exploits information of functionality from go combined with the network topology. lcda-go identifies the community of each protein based on the topological and functional knowledge acquired solely from the local neighbour proteins within the ppi network. Experimental results using the Krogan dataset demonstrate that our algorithm outperforms in most cases state-of-the-art approaches in assessment based on Precision, Sensitivity, and particularly Composite Score. We also deployed lcda, the local-topology based precursor of lcda-go, to compare with a similar state-of-the-art approach that exclusively incorporates topological information of ppi networks for community detection. In addition to the high quality of the results, one main advantage of lcda-go is its low computational time complexity.

Double-layer clustering method to predict protein complexes based on power-law distribution and protein sublocalization

Predicting protein complexes in protein interaction networks using Mapper and graph convolution networks

Proteins complexes accomplish biological functions such as transcription of DNA and translation of mRNA. Detecting protein complexes correctly and efficiently is becoming a challenging task. This paper presents a novel algorithm, core-attachment based on ant colony optimization (CA-ACO), which detects complexes in three stages. Firstly, initialize the similarity matrix. Secondly, complexes are predicted by clustering in the dynamic PPI networks. In the step, the clustering coefficient of every node is also computed. A node whose clustering coefficient is greater than the threshold is added to the core protein set. Then we mark every neighbor node of core proteins with unique core label during picking and dropping. Thirdly, filtering processes are carried out to obtain the final complex set. Experimental results show that CA-ACO algorithm had great superiority in precision, recall and f-measure compared with the state-of-the-art methods such as ClusterONE, DPClus, MCODE and so on.

Nowadays, cluster analysis of biological networks has become one of the most important approaches to identifying functional modules as well as predicting protein complexes and network biomarkers. Furthermore, the visualization of clustering results is crucial to display the structure of biological networks. Here we present CytoCluster, a cytoscape plugin integrating six clustering algorithms, HC-PIN (Hierarchical Clustering algorithm in Protein Interaction Networks), OH-PIN (identifying Overlapping and Hierarchical modules in Protein Interaction Networks), IPCA (Identifying Protein Complex Algorithm), ClusterONE (Clustering with Overlapping Neighborhood Expansion), DCU (Detecting Complexes based on Uncertain graph model), IPC-MCE (Identifying Protein Complexes based on Maximal Complex Extension), and BinGO (the Biological networks Gene Ontology) function. Users can select different clustering algorithms according to their requirements. The main function of these six clustering algorithms is to detect protein complexes or functional modules. In addition, BinGO is used to determine which Gene Ontology (GO) categories are statistically overrepresented in a set of genes or a subgraph of a biological network. CytoCluster can be easily expanded, so that more clustering algorithms and functions can be added to this plugin. Since it was created in July 2013, CytoCluster has been downloaded more than 9700 times in the Cytoscape App store and has already been applied to the analysis of different biological networks. CytoCluster is available from http://apps.cytoscape.org/apps/cytocluster.

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

Proteins interact with other proteins and bio-molecules to form a complex and execute key biological functions in a living organism, and respond to several environmental signals. Designing efficient predictive models for protein complexes is a challenging task with limited coverage in the contemporary literature. With this motivation, we have developed a novel method, PCPredG, for 3-node protein complex prediction from PPI networks using 5-node graphlet features. CORUM protein complex repository has been used to curate positive and negative data samples with the help of MCODE and MCL clustering algorithms. During experiments, Random Forest(RF) and SVM classifiers are trained with 1000 positive 3-node complexes in 10-fold cross-validation setup and with 1:1 to 1:10 positive-negative proportions. In parallel, we have implemented the state-of-the-art GCN with polarised message-passing, GAT and an ensemble of GCN and GAT in both balanced and imbalanced setups. We also introduced a 10-fold quality consensus on the hold-out set across all the experiments. We have achieved the best performances with the RF classifier in both balanced and imbalanced experiments.

BackgroundIdentification of protein complexes in large interaction networks is crucial to understand principles of cellular organization and predict protein functions, which is one of the most important issues in the post-genomic era. Each protein might be subordinate multiple protein complexes in the real protein-protein interaction networks. Identifying overlapping protein complexes from protein-protein interaction networks is a considerable research topic.ResultAs an effective algorithm in identifying overlapping module structures, clique percolation method (CPM) has a wide range of application in social networks and biological networks. However, the recognition accuracy of algorithm CPM is lowly. Furthermore, algorithm CPM is unfit to identifying protein complexes with meso-scale when it applied in protein-protein interaction networks. In this paper, we propose a new topological model by extending the definition of k-clique community of algorithm CPM and introduced distance restriction, and develop a novel algorithm called CP-DR based on the new topological model for identifying protein complexes. In this new algorithm, the protein complex size is restricted by distance constraint to conquer the shortcomings of algorithm CPM. The algorithm CP-DR is applied to the protein interaction network of Sacchromyces cerevisiae and identifies many well known complexes.ConclusionThe proposed algorithm CP-DR based on clique percolation and distance restriction makes it possible to identify dense subgraphs in protein interaction networks, a large number of which correspond to known protein complexes. Compared to algorithm CPM, algorithm CP-DR has more outstanding performance.

BackgroundHigh-throughput methods for detecting protein-protein interactions enable us to obtain large interaction networks, and also allow us to computationally identify the associations of proteins as protein complexes. Although there are methods to extract protein complexes as sets of proteins from interaction networks, the extracted complexes may include false positives because they do not account for the structural limitations of the proteins and thus do not check that the proteins in the extracted complex can simultaneously bind to each other. In addition, there have been few searches for deeper insights into the protein complexes, such as of the topology of the protein-protein interactions or into the domain-domain interactions that mediate the protein interactions.ResultsHere, we introduce a combinatorial approach for prediction of protein complexes focusing not only on determining member proteins in complexes but also on the DDI/PPI organization of the complexes. Our method analyzes complex candidates predicted by the existing methods. It searches for optimal combinations of domain-domain interactions in the candidates based on an assumption that the proteins in a candidate can form a true protein complex if each of the domains is used by a single protein interaction. This optimization problem was mathematically formulated and solved using binary integer linear programming. By using publicly available sets of yeast protein-protein interactions and domain-domain interactions, we succeeded in extracting protein complex candidates with an accuracy that is twice the average accuracy of the existing methods, MCL, MCODE, or clustering coefficient. Although the configuring parameters for each algorithm resulted in slightly improved precisions, our method always showed better precision for most values of the parameters.ConclusionsOur combinatorial approach can provide better accuracy for prediction of protein complexes and also enables to identify both direct PPIs and DDIs that mediate them in complexes.

Network clustering is employed in bioinformatics and data mining studies to investigate the structural and functional properties of protein-protein interaction (PPI) networks. In multiple studies over the past two decades, network clustering has proven valuable for uncovering functional modules and elucidating the functions of previously undiscovered proteins. Protein complexes are vital cellular components that play a crucial role in generating biological activity. Experimental techniques have inherent limitations in inferring protein complexes. Given these constraints, numerous computational methods have emerged over the past decade for predicting protein complexes. Typically, these methods take the input PPI data and generate predicted protein complexes as output subnetworks. Most of these methods have shown encouraging outcomes in predicting protein complexes. Prediction is challenging for sparse, small, and overlapping complexes. New strategies should include explicit knowledge about the biological characteristics of proteins to increase performance. Furthermore, specific issues should be considered more effectively in the future while developing new complex prediction algorithms. The bioinformatics community has developed various techniques for clustering PPI networks, which we identified, analyzed, and compared in this paper. This review evaluates various graph clustering algorithms for protein complex identification, facilitating the benchmarking of existing methods, identifying limitations, motivating the development of novel computational tools, and ultimately improving biological insight and therapeutic progress. Through the assessment of strengths and limitations, researchers may develop efficient and scalable algorithms designed explicitly for biological data, integrating graph-based methodologies with machine learning and deep learning approaches. This study is an invaluable tool for new researchers in the area to recognize upcoming trends, including dynamic PPI networks and temporal complex identification.

Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1-/y mice, the unstimulated protein interaction network state resembled that of wildtype littermates stimulated with mGluR agonists, demonstrating resting state pre-activation of mGluR signaling networks. In contrast, interactions downstream of NMDAR stimulation were similar to WT. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated in FMR1-/y animals. We tested whether targeting SFKs in FMR1-/y mice could modify disease phenotypes, and found that Saracatinib (SCB), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1-/y mice. However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.

The identification of temporal protein complexes would make great contribution to our knowledge of the dynamic organization characteristics in protein interaction networks (PINs). Recent studies have focused on integrating gene expression data into static PIN to construct dynamic PIN which reveals the dynamic evolutionary procedure of protein interactions, but they fail in practice for recognizing the active time points of proteins with low or high expression levels. We construct a Time-Evolving PIN (TEPIN) with a novel method called Deviation Degree, which is designed to identify the active time points of proteins based on the deviation degree of their own expression values. Owing to the differences between protein interactions, moreover, we weight TEPIN with connected affinity and gene co-expression to quantify the degree of these interactions. To validate the efficiencies of our methods, ClusterONE, CAMSE and MCL algorithms are applied on the TEPIN, DPIN (a dynamic PIN constructed with state-of-the-art three-sigma method) and SPIN (the original static PIN) to detect temporal protein complexes. Each algorithm on our TEPIN outperforms that on other networks in terms of match degree, sensitivity, specificity, F-measure and function enrichment etc. In conclusion, our Deviation Degree method successfully eliminates the disadvantages which exist in the previous state-of-the-art dynamic PIN construction methods. Moreover, the biological nature of protein interactions can be well described in our weighted network. Weighted TEPIN is a useful approach for detecting temporal protein complexes and revealing the dynamic protein assembly process for cellular organization.

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.