Methods for protein complex prediction and their contributions towards understanding the organization, function and dynamics of complexes

Complexes of physically interacting proteins constitute fundamental functional units responsible for driving biological processes within cells. A faithful reconstruction of the entire set of complexes is therefore essential to understand the functional organization of cells. In this review, we discuss the key contributions of computational methods developed till date (approximately between 2003 and 2015) for identifying complexes from the network of interacting proteins (PPI network). We evaluate in depth the performance of these methods on PPI datasets from yeast, and highlight challenges faced by these methods, in particular detection of sparse and small or sub- complexes and discerning of overlapping complexes. We describe methods for integrating diverse information including expression profiles and 3D structures of proteins with PPI networks to understand the dynamics of complex formation, for instance, of time-based assembly of complex subunits and formation of fuzzy complexes from intrinsically disordered proteins. Finally, we discuss methods for identifying dysfunctional complexes in human diseases, an application that is proving invaluable to understand disease mechanisms and to discover novel therapeutic targets. We hope this review aptly commemorates a decade of research on computational prediction of complexes and constitutes a valuable reference for further advancements in this exciting area.Comment: 1 Tabl

Mining Maximal Cliques from an Uncertain Graph

We consider mining dense substructures (maximal cliques) from an uncertain graph, which is a probability distribution on a set of deterministic graphs. For parameter 0 < {\alpha} < 1, we present a precise definition of an {\alpha}-maximal clique in an uncertain graph. We present matching upper and lower bounds on the number of {\alpha}-maximal cliques possible within an uncertain graph. We present an algorithm to enumerate {\alpha}-maximal cliques in an uncertain graph whose worst-case runtime is near-optimal, and an experimental evaluation showing the practical utility of the algorithm.Comment: ICDE 201

Parallel Maximum Clique Algorithms with Applications to Network Analysis and Storage

We propose a fast, parallel maximum clique algorithm for large sparse graphs that is designed to exploit characteristics of social and information networks. The method exhibits a roughly linear runtime scaling over real-world networks ranging from 1000 to 100 million nodes. In a test on a social network with 1.8 billion edges, the algorithm finds the largest clique in about 20 minutes. Our method employs a branch and bound strategy with novel and aggressive pruning techniques. For instance, we use the core number of a vertex in combination with a good heuristic clique finder to efficiently remove the vast majority of the search space. In addition, we parallelize the exploration of the search tree. During the search, processes immediately communicate changes to upper and lower bounds on the size of maximum clique, which occasionally results in a super-linear speedup because vertices with large search spaces can be pruned by other processes. We apply the algorithm to two problems: to compute temporal strong components and to compress graphs.Comment: 11 page

ProCbA: Protein Function Prediction based on Clique Analysis

Protein function prediction based on protein-protein interactions (PPI) is one of the most important challenges of the post-Genomic era. Due to the fact that determining protein function by experimental techniques can be costly, function prediction has become an important challenge for computational biology and bioinformatics. Some researchers utilize graph- (or network-) based methods using PPI networks for unannotated proteins. The aim of this study is to increase the accuracy of the protein function prediction using two proposed methods. To predict protein functions, we propose a Protein Function Prediction based on Clique Analysis (ProCbA) and Protein Function Prediction on Neighborhood Counting using functional aggregation (ProNC-FA). Both ProCbA and ProNC-FA can predict the functions of unknown proteins. In addition, in ProNC-FA which does not include a new algorithm; we attempt to solve the essence of incomplete and noisy data of the PPI era in order to achieve a network with complete functional aggregation. The experimental results on MIPS data and the 17 different explained datasets validate the encouraging performance and the strength of both ProCbA and ProNC-FA on function prediction. Experimental result analysis demonstrates that both ProCbA and ProNC-FA are generally able to outperform all the other methods

Recent advances in clustering methods for protein interaction networks

The increasing availability of large-scale protein-protein interaction data has made it possible to understand the basic components and organization of cell machinery from the network level. The arising challenge is how to analyze such complex interacting data to reveal the principles of cellular organization, processes and functions. Many studies have shown that clustering protein interaction network is an effective approach for identifying protein complexes or functional modules, which has become a major research topic in systems biology. In this review, recent advances in clustering methods for protein interaction networks will be presented in detail. The predictions of protein functions and interactions based on modules will be covered. Finally, the performance of different clustering methods will be compared and the directions for future research will be discussed

Identifying protein complexes and disease genes from biomolecular networks

With advances in high-throughput measurement techniques, large-scale biological data, such as protein-protein interaction (PPI) data, gene expression data, gene-disease association data, cellular pathway data, and so on, have been and will continue to be produced. Those data contain insightful information for understanding the mechanisms of biological systems and have been proved useful for developing new methods in disease diagnosis, disease treatment and drug design. This study focuses on two main research topics: (1) identifying protein complexes and (2) identifying disease genes from biomolecular networks. Firstly, protein complexes are groups of proteins that interact with each other at the same time and place within living cells. They are molecular entities that carry out cellular processes. The identification of protein complexes plays a primary role for understanding the organization of proteins and the mechanisms of biological systems. Many previous algorithms are designed based on the assumption that protein complexes are densely connected sub-graphs in PPI networks. In this research, a dense sub-graph detection algorithm is first developed following this assumption by using clique seeds and graph entropy. Although the proposed algorithm generates a large number of reasonable predictions and its f-score is better than many previous algorithms, it still cannot identify many known protein complexes. After that, we analyze characteristics of known yeast protein complexes and find that not all of the complexes exhibit dense structures in PPI networks. Many of them have a star-like structure, which is a very special case of the core-attachment structure and it cannot be identified by many previous core-attachment-structure-based algorithms. To increase the prediction accuracy of protein complex identification, a multiple-topological-structure-based algorithm is proposed to identify protein complexes from PPI networks. Four single-topological-structure-based algorithms are first employed to detect raw predictions with clique, dense, core-attachment and star-like structures, respectively. A merging and trimming step is then adopted to generate final predictions based on topological information or GO annotations of predictions. A comprehensive review about the identification of protein complexes from static PPI networks to dynamic PPI networks is also given in this study. Secondly, genetic diseases often involve the dysfunction of multiple genes. Various types of evidence have shown that similar disease genes tend to lie close to one another in various biomolecular networks. The identification of disease genes via multiple data integration is indispensable towards the understanding of the genetic mechanisms of many genetic diseases. However, the number of known disease genes related to similar genetic diseases is often small. It is not easy to capture the intricate gene-disease associations from such a small number of known samples. Moreover, different kinds of biological data are heterogeneous and no widely acceptable criterion is available to standardize them to the same scale. In this study, a flexible and reliable multiple data integration algorithm is first proposed to identify disease genes based on the theory of Markov random fields (MRF) and the method of Bayesian analysis. A novel global-characteristic-based parameter estimation method and an improved Gibbs sampling strategy are introduced, such that the proposed algorithm has the capability to tune parameters of different data sources automatically. However, the Markovianity characteristic of the proposed algorithm means it only considers information of direct neighbors to formulate the relationship among genes, ignoring the contribution of indirect neighbors in biomolecular networks. To overcome this drawback, a kernel-based MRF algorithm is further proposed to take advantage of the global characteristics of biological data via graph kernels. The kernel-based MRF algorithm generates predictions better than many previous disease gene identification algorithms in terms of the area under the receiver operating characteristic curve (AUC score). However, it is very time-consuming, since the Gibbs sampling process of the algorithm has to maintain a long Markov chain for every single gene. Finally, to reduce the computational time of the MRF-based algorithm, a fast and high performance logistic-regression-based algorithm is developed for identifying disease genes from biomolecular networks. Numerical experiments show that the proposed algorithm outperforms many existing methods in terms of the AUC score and running time. To summarize, this study has developed several computational algorithms for identifying protein complexes and disease genes from biomolecular networks, respectively. These proposed algorithms are better than many other existing algorithms in the literature

Accuracy improvement in protein complex prediction from protein interaction networks by refining cluster overlaps

<p>Abstract</p> <p>Background</p> <p>Recent computational techniques have facilitated analyzing genome-wide protein-protein interaction data for several model organisms. Various graph-clustering algorithms have been applied to protein interaction networks on the genomic scale for predicting the entire set of potential protein complexes. In particular, the density-based clustering algorithms which are able to generate overlapping clusters, i.e. the clusters sharing a set of nodes, are well-suited to protein complex detection because each protein could be a member of multiple complexes. However, their accuracy is still limited because of complex overlap patterns of their output clusters.</p> <p><b>Results</b></p> <p>We present a systematic approach of refining the overlapping clusters identified from protein interaction networks. We have designed novel metrics to assess cluster overlaps: overlap coverage and overlapping consistency. We then propose an overlap refinement algorithm. It takes as input the clusters produced by existing density-based graph-clustering methods and generates a set of refined clusters by parameterizing the metrics. To evaluate protein complex prediction accuracy, we used the <it>f</it>-measure by comparing each refined cluster to known protein complexes. The experimental results with the yeast protein-protein interaction data sets from BioGRID and DIP demonstrate that accuracy on protein complex prediction has increased significantly after refining cluster overlaps.</p> <p><b>Conclusions</b></p> <p>The effectiveness of the proposed cluster overlap refinement approach for protein complex detection has been validated in this study. Analyzing overlaps of the clusters from protein interaction networks is a crucial task for understanding of functional roles of proteins and topological characteristics of the functional systems.</p

Network-assisted protein identification and data interpretation in shotgun proteomics

Protein assembly and biological interpretation of the assembled protein lists are critical steps in shotgun proteomics data analysis. Although most biological functions arise from interactions among proteins, current protein assembly pipelines treat proteins as independent entities. Usually, only individual proteins with strong experimental evidence, that is, confident proteins, are reported, whereas many possible proteins of biological interest are eliminated. We have developed a clique-enrichment approach (CEA) to rescue eliminated proteins by incorporating the relationship among proteins as embedded in a protein interaction network. In several data sets tested, CEA increased protein identification by 8–23% with an estimated accuracy of 85%. Rescued proteins were supported by existing literature or transcriptome profiling studies at similar levels as confident proteins and at a significantly higher level than abandoned ones. Applying CEA on a breast cancer data set, rescued proteins coded by well-known breast cancer genes. In addition, CEA generated a network view of the proteins and helped show the modular organization of proteins that may underpin the molecular mechanisms of the disease

Link Prediction in Complex Networks: A Survey

Link prediction in complex networks has attracted increasing attention from both physical and computer science communities. The algorithms can be used to extract missing information, identify spurious interactions, evaluate network evolving mechanisms, and so on. This article summaries recent progress about link prediction algorithms, emphasizing on the contributions from physical perspectives and approaches, such as the random-walk-based methods and the maximum likelihood methods. We also introduce three typical applications: reconstruction of networks, evaluation of network evolving mechanism and classification of partially labelled networks. Finally, we introduce some applications and outline future challenges of link prediction algorithms.Comment: 44 pages, 5 figure

Reconstruction of human protein interolog network using evolutionary conserved network

<p>Abstract</p> <p>Background</p> <p>The recent increase in the use of high-throughput two-hybrid analysis has generated large quantities of data on protein interactions. Specifically, the availability of information about experimental protein-protein interactions and other protein features on the Internet enables human protein-protein interactions to be computationally predicted from co-evolution events (interolog). This study also considers other protein interaction features, including sub-cellular localization, tissue-specificity, the cell-cycle stage and domain-domain combination. Computational methods need to be developed to integrate these heterogeneous biological data to facilitate the maximum accuracy of the human protein interaction prediction.</p> <p>Results</p> <p>This study proposes a relative conservation score by finding maximal quasi-cliques in protein interaction networks, and considering other interaction features to formulate a scoring method. The scoring method can be adopted to discover which protein pairs are the most likely to interact among multiple protein pairs. The predicted human protein-protein interactions associated with confidence scores are derived from six eukaryotic organisms – rat, mouse, fly, worm, thale cress and baker's yeast.</p> <p>Conclusion</p> <p>Evaluation results of the proposed method using functional keyword and Gene Ontology (GO) annotations indicate that some confidence is justified in the accuracy of the predicted interactions. Comparisons among existing methods also reveal that the proposed method predicts human protein-protein interactions more accurately than other interolog-based methods.</p