Real Protein-protein Interaction Networks Research Articles

Multi-SANA: Comparing Measures of Topological Similarity for Multiple Network Alignment

All life on Earth is related, so that some molecular interactions are common across almost all living cells, with the number of common interactions increasing as we look at more closely related species. In particular, we expect the protein–protein interaction (PPI) networks of closely related species to share high levels of similarity. This similarity may facilitate the transfer of functional knowledge between model species and human. Multiple network alignment is the process of uncovering the connection similarity between three or more networks simultaneously. Existing algorithms for multiple network alignment rely on sequence similarities to help drive the alignments, and no comprehensive study has been done to determine the most effective ways to utilize network connectivity—network topology—to drive multiple network alignment. Here, we devise and empirically test the efficacy of several measures of topological similarity between three or more networks. To evolve the alignments toward optimal, we use simulated annealing as the search algorithm since it is agnostic to the objective being optimized. We test the measures both on the partially synthetic and highly similar PPI networks from the integrated interaction database, as well as on real PPI networks from a recent BioGRID release.

NAPAbench 2: A network synthesis algorithm for generating realistic protein-protein interaction (PPI) network families.

Comparative network analysis provides effective computational means for gaining novel insights into the structural and functional compositions of biological networks. In recent years, various methods have been developed for biological network alignment, whose main goal is to identify important similarities and critical differences between networks in terms of their topology and composition. A major impediment to advancing network alignment techniques has been the lack of gold-standard benchmarks that can be used for accurate and comprehensive performance assessment of such algorithms. The original NAPAbench (network alignment performance assessment benchmark) was developed to address this problem, and it has been widely utilized by many researchers for the development, evaluation, and comparison of novel network alignment techniques. In this work, we introduce NAPAbench 2—a major update of the original NAPAbench that was introduced in 2012. NAPAbench 2 includes a completely redesigned network synthesis algorithm that can generate protein-protein interaction (PPI) network families whose characteristics closely match those of the latest real PPI networks. Furthermore, the network synthesis algorithm comes with an intuitive GUI that allows users to easily generate PPI network families with an arbitrary number of networks of any size, according to a flexible user-defined phylogeny. In addition, NAPAbench 2 provides updated benchmark datasets—created using the redesigned network synthesis algorithm—which can be used for comprehensive performance assessment of network alignment algorithms and their scalability.

Using Alias Sampling Strategy Based on Network Embeddings to Detect Protein Complexes

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.

A Robust Algorithm Based on Link Label Propagation for Identifying Functional Modules From Protein-Protein Interaction Networks.

Identifying functional modules in protein-protein interaction (PPI) networks elucidates cellular organization and mechanism. Various methods have been proposed to identify the functional modules in PPI networks, but most of these methods do not consider the noisy links in PPI networks. They achieve a competitive performance on the PPI networks without noisy links, but the performance of these methods considerably deteriorates in the noisy PPI networks. Furthermore, the noisy links are inevitable in the PPI networks. In this paper, we propose a novel link-driven label propagation algorithm (LLPA) to identify functional modules in PPI networks. The LLPA first find link clusters in PPI networks, and then the functional modules are identified from the link clusters. Two strategies aimed to ensure the robustness of LLPA are proposed. One strategy involves the proposed LLPA updating the link labels in accordance with the designed weight of the link, which can reduce the incidence of noisy links. The other strategy involves the filtration of some noisy labels from the link clusters to further reduce the influence of noisy links. The performance evaluation on three real PPI networks shows that LLPA outperforms other eight state-of-the-art detection algorithms in terms of accuracy and robustness.

Refining modules to determine functionally significant clusters in molecular networks

BackgroundModule detection algorithms relying on modularity maximization suffer from an inherent resolution limit that hinders detection of small topological modules, especially in molecular networks where most biological processes are believed to form small and compact communities. We propose a novel modular refinement approach that helps finding functionally significant modules of molecular networks.ResultsThe module refinement algorithm improves the quality of topological modules in protein-protein interaction networks by finding biologically functionally significant modules. The algorithm is based on the fact that functional modules in biology do not necessarily represent those corresponding to maximum modularity. Larger modules corresponding to maximal modularity are incrementally re-modularized again under specific constraints so that smaller yet topologically and biologically valid modules are recovered. We show improvement in quality and functional coverage of modules using experiments on synthetic and real protein-protein interaction networks. We also compare our results with six existing methods available for clustering biological networks.ConclusionThe proposed algorithm finds smaller but functionally relevant modules that are undetected by classical quality maximization approaches for modular detection. The refinement procedure helps to detect more functionally enriched modules in protein-protein interaction networks, which are also more coherent with functionally characterised gene sets.

ConnectedAlign: a PPI network alignment method for identifying conserved protein complexes across multiple species

BackgroundIn bioinformatics, network alignment algorithms have been applied to protein-protein interaction (PPI) networks to discover evolutionary conserved substructures at the system level. However, most previous methods aim to maximize the similarity of aligned proteins in pairwise networks, while concerning little about the feature of connectivity in these substructures, such as the protein complexes.ResultsIn this paper, we identify the problem of finding conserved protein complexes, which requires the aligned proteins in a PPI network to form a connected subnetwork. By taking the feature of connectivity into consideration, we propose ConnectedAlign, an efficient method to find conserved protein complexes from multiple PPI networks. The proposed method improves the coverage significantly without compromising of the consistency in the aligned results. In this way, the knowledge of protein complexes in well-studied species can be extended to that of poor-studied species.ConclusionsWe conducted extensive experiments on real PPI networks of four species, including human, yeast, fruit fly and worm. The experimental results demonstrate dominant benefits of the proposed method in finding protein complexes across multiple species.

Effective comparative analysis of protein-protein interaction networks by measuring the steady-state network flow using a Markov model.

BackgroundComparative analysis of protein-protein interaction (PPI) networks provides an effective means of detecting conserved functional network modules across different species. Such modules typically consist of orthologous proteins with conserved interactions, which can be exploited to computationally predict the modules through network comparison.ResultsIn this work, we propose a novel probabilistic framework for comparing PPI networks and effectively predicting the correspondence between proteins, represented as network nodes, that belong to conserved functional modules across the given PPI networks. The basic idea is to estimate the steady-state network flow between nodes that belong to different PPI networks based on a Markov random walk model. The random walker is designed to make random moves to adjacent nodes within a PPI network as well as cross-network moves between potential orthologous nodes with high sequence similarity. Based on this Markov random walk model, we estimate the steady-state network flow – or the long-term relative frequency of the transitions that the random walker makes – between nodes in different PPI networks, which can be used as a probabilistic score measuring their potential correspondence. Subsequently, the estimated scores can be used for detecting orthologous proteins in conserved functional modules through network alignment.ConclusionsThrough evaluations based on multiple real PPI networks, we demonstrate that the proposed scheme leads to improved alignment results that are biologically more meaningful at reduced computational cost, outperforming the current state-of-the-art algorithms. The source code and datasets can be downloaded from http://www.ece.tamu.edu/~bjyoon/CUFID.

Joint Alignment of Multiple Protein–Protein Interaction Networks via Convex Optimization

High-throughput experimental techniques have been producing more and more protein-protein interaction (PPI) data. The PPI network alignment greatly benefits the understanding of evolutionary relationship among species, helps identify conserved subnetworks, and provides extra information for functional annotations. Although a few methods have been developed for multiple PPI network alignment, the alignment quality is still far from perfect, and thus, new network alignment methods are needed. In this article, we present a novel method, denoted as ConvexAlign, for joint alignment of multiple PPI networks by convex optimization of a scoring function composed of sequence similarity, topological score, and interaction conservation score. In contrast to existing methods that generate multiple alignments in a greedy or progressive manner, our convex method optimizes alignments globally and enforces consistency among all pairwise alignments, resulting in much better alignment quality. Tested on both synthetic and real data, our experimental results show that ConvexAlign outperforms several popular methods in producing functionally coherent alignments. ConvexAlign even has a larger advantage over the others in aligning real PPI networks. ConvexAlign also finds a few conserved complexes, which cannot be detected by the other methods.

Protein Function Prediction Based on Active Semi‐supervised Learning

In our study, the active learning and semisupervised learning methods are comprehensively used for label delivery of proteins with known functions in Proteinprotein interaction (PPI) network so as to predict the functions of unknown proteins. Because the real PPI network is generally observed with overlapping protein nodes with multiple functions, the mislabeling of overlapping protein may result in accumulation of prediction errors. For this reason, prior to executing the label delivery process of semi-supervised learning, the adjacency matrix is used to detect overlapping proteins. As the topological structure description of interactive relation between proteins, PPI network is observed with party hub protein nodes that play an important role, in co-expression with its neighborhood. Therefore, to reduce the manual labeling cost, party hub proteins most beneficial for improvement of prediction accuracy are selected for class labeling and the labeled party hub proteins are added into the labeled sample set for semisupervised learning later. As the experimental results of real yeast PPI network show, the proposed algorithm can achieve high prediction accuracy with few labeled samples.

Mean field theory for biology inspired duplication-divergence network model

The duplication-divergence network model is generally thought to incorporate key ingredients underlying the growth and evolution of protein-protein interaction networks. Properties of the model have been elucidated through numerous simulation studies. However, a comprehensive theoretical study of the model is lacking. Here, we derived analytic expressions for quantities describing key characteristics of the network-the average degree, the degree distribution, the clustering coefficient, and the neighbor connectivity-in the mean-field, large-N limit of an extended version of the model, duplication-divergence complemented with heterodimerization and addition. We carried out extensive simulations and verified excellent agreement between simulation and theory except for one partial case. All four quantities obeyed power-laws even at moderate network size ( N∼10(4)), except the degree distribution, which had an additional exponential factor observed to obey power-law. It is shown that our network model can lead to the emergence of scale-free property and hierarchical modularity simultaneously, reproducing the important topological properties of real protein-protein interaction networks.

Dynamics of the discovery process of protein-protein interactions from low content studies.

BackgroundThousands of biological and biomedical investigators study of the functional role of single genes and their protein products in normal physiology and in disease. The findings from these studies are reported in research articles that stimulate new research. It is now established that a complex regulatory networks's is controlling human cellular fate, and this community of researchers are continually unraveling this network topology. Attempts to integrate results from such accumulated knowledge resulted in literature-based protein-protein interaction networks (PPINs) and pathway databases. These databases are widely used by the community to analyze new data collected from emerging genome-wide studies with the assumption that the data within these literature-based databases is the ground truth and contain no biases. While suspicion for research focus biases is growing, a concrete proof for it is still missing. It is difficult to prove because the real PPINs are mostly unknown.ResultsHere we analyzed the longitudinal discovery process of literature-based mammalian and yeast PPINs to observe that these networks are discovered non-uniformly. The pattern of discovery is related to a theoretical concept proposed by Kauffman called “expanding the adjacent possible”. We introduce a network discovery model which explicitly includes the space of possibilities in the form of a true underlying PPIN.ConclusionsOur model strongly suggests that research focus biases exist in the observed discovery dynamics of these networks. In summary, more care should be placed when using PPIN databases for analysis of newly acquired data, and when considering prior knowledge when designing new experiments.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0173-z) contains supplementary material, which is available to authorized users.

Yeast protein-protein interaction network model based on biological experimental data

Duplication and divergence have been widely recognized as the two dominant evolutionary forces in shaping biological networks, e.g., gene regulatory networks and protein-protein interaction (PPI) networks. It has been shown that the network growth models constructed on the principle of duplication and divergence can recapture the topological properties of real PPI networks. However, such network models only consider the evolution processes. How to select the model parameters with the real biological experimental data has not been presented. Therefore, based on the real PPI network statistical data, a yeast PPI network model is constructed. The simulation results indicate that the topological characteristics of the constructed network model are well consistent with those of real PPI networks, especially on sparseness, scale-free, small-world, hierarchical modularity, and disassortativity.

Accurate multiple network alignment through context-sensitive random walk.

BackgroundComparative network analysis can provide an effective means of analyzing large-scale biological networks and gaining novel insights into their structure and organization. Global network alignment aims to predict the best overall mapping between a given set of biological networks, thereby identifying important similarities as well as differences among the networks. It has been shown that network alignment methods can be used to detect pathways or network modules that are conserved across different networks. Until now, a number of network alignment algorithms have been proposed based on different formulations and approaches, many of them focusing on pairwise alignment.ResultsIn this work, we propose a novel multiple network alignment algorithm based on a context-sensitive random walk model. The random walker employed in the proposed algorithm switches between two different modes, namely, an individual walk on a single network and a simultaneous walk on two networks. The switching decision is made in a context-sensitive manner by examining the current neighborhood, which is effective for quantitatively estimating the degree of correspondence between nodes that belong to different networks, in a manner that sensibly integrates node similarity and topological similarity. The resulting node correspondence scores are then used to predict the maximum expected accuracy (MEA) alignment of the given networks.ConclusionsPerformance evaluation based on synthetic networks as well as real protein-protein interaction networks shows that the proposed algorithm can construct more accurate multiple network alignments compared to other leading methods.

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

BackgroundDetecting 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.MethodsThis 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.ResultsThe 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.

Graphlet-based measures are suitable for biological network comparison

Large amounts of biological network data exist for many species. Analogous to sequence comparison, network comparison aims to provide biological insight. Graphlet-based methods are proving to be useful in this respect. Recently some doubt has arisen concerning the applicability of graphlet-based measures to low edge density networks-in particular that the methods are 'unstable'-and further that no existing network model matches the structure found in real biological networks. We demonstrate that it is the model networks themselves that are 'unstable' at low edge density and that graphlet-based measures correctly reflect this instability. Furthermore, while model network topology is unstable at low edge density, biological network topology is stable. In particular, one must distinguish between average density and local density. While model networks of low average edge densities also have low local edge density, that is not the case with protein-protein interaction (PPI) networks: real PPI networks have low average edge density, but high local edge densities, and hence, they (and thus graphlet-based measures) are stable on these networks. Finally, we use a recently devised non-parametric statistical test to demonstrate that PPI networks of many species are well-fit by several models not previously tested. In addition, we model several viral PPI networks for the first time and demonstrate an exceptionally good fit between the data and theoretical models.

Clustering Large Probabilistic Graphs

We study the problem of clustering probabilistic graphs. Similar to the problem of clustering standard graphs, probabilistic graph clustering has numerous applications, such as finding complexes in probabilistic protein-protein interaction (PPI) networks and discovering groups of users in affiliation networks. We extend the edit-distance-based definition of graph clustering to probabilistic graphs. We establish a connection between our objective function and correlation clustering to propose practical approximation algorithms for our problem. A benefit of our approach is that our objective function is parameter-free. Therefore, the number of clusters is part of the output. We also develop methods for testing the statistical significance of the output clustering and study the case of noisy clusterings. Using a real protein-protein interaction network and ground-truth data, we show that our methods discover the correct number of clusters and identify established protein relationships. Finally, we show the practicality of our techniques using a large social network of Yahoo! users consisting of one billion edges.

Identifying functional modules in interaction networks through overlapping Markov clustering

Motivation: In recent years, Markov clustering (MCL) has emerged as an effective algorithm for clustering biological networks—for instance clustering protein–protein interaction (PPI) networks to identify functional modules. However, a limitation of MCL and its variants (e.g. regularized MCL) is that it only supports hard clustering often leading to an impedance mismatch given that there is often a significant overlap of proteins across functional modules.Results: In this article, we seek to redress this limitation. We propose a soft variation of Regularized MCL (R-MCL) based on the idea of iteratively (re-)executing R-MCL while ensuring that multiple executions do not always converge to the same clustering result thus allowing for highly overlapped clusters. The resulting algorithm, denoted soft regularized Markov clustering, is shown to outperform a range of extant state-of-the-art approaches in terms of accuracy of identifying functional modules on three real PPI networks.Availability: All data and codes are freely available upon request.Contact: srini@cse.ohio-state.eduSupplementary Information: Supplementary data are available at Bioinformatics online.

A Network Synthesis Model for Generating Protein Interaction Network Families

In this work, we introduce a novel network synthesis model that can generate families of evolutionarily related synthetic protein–protein interaction (PPI) networks. Given an ancestral network, the proposed model generates the network family according to a hypothetical phylogenetic tree, where the descendant networks are obtained through duplication and divergence of their ancestors, followed by network growth using network evolution models. We demonstrate that this network synthesis model can effectively create synthetic networks whose internal and cross-network properties closely resemble those of real PPI networks. The proposed model can serve as an effective framework for generating comprehensive benchmark datasets that can be used for reliable performance assessment of comparative network analysis algorithms. Using this model, we constructed a large-scale network alignment benchmark, called NAPAbench, and evaluated the performance of several representative network alignment algorithms. Our analysis clearly shows the relative performance of the leading network algorithms, with their respective advantages and disadvantages. The algorithm and source code of the network synthesis model and the network alignment benchmark NAPAbench are publicly available at http://www.ece.tamu.edu/bjyoon/NAPAbench/.

An overlapping module identification method in protein-protein interaction networks

BackgroundPrevious studies have shown modular structures in PPI (protein-protein interaction) networks. More recently, many genome and metagenome investigations have focused on identifying modules in PPI networks. However, most of the existing methods are insufficient when applied to networks with overlapping modular structures. In our study, we describe a novel overlapping module identification method (OMIM) to address this problem.ResultsOur method is an agglomerative clustering method merging modules according to their contributions to modularity. Nodes that have positive effects on more than two modules are defined as overlapping parts. As well, we designed de-noising steps based on a clustering coefficient and hub finding steps based on nodal weight.ConclusionsThe low computational complexity and few control parameters prove that our method is suitable for large scale PPI network analysis. First, we verified OMIM on a small artificial word association network which was able to provide us with a comprehensive evaluation. Then experiments on real PPI networks from the MIPS Saccharomyces Cerevisiae dataset were carried out. The results show that OMIM outperforms several other popular methods in identifying high quality modular structures.

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

BackgroundNetwork 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.MethodsWe 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).ResultsWhen 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.ConclusionsWe 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.