Properties Of Protein-protein Interaction Networks Research Articles

Exploring the druggable proteome of Candida species through comprehensive computational analysis

Candida albicans and non-albicans Candida spp. are major cause of systemic mycoses. Antifungal drugs such as azoles and polyenes are not efficient to successfully eradicate Candida infection owing to their fungistatic nature or low bioavailability. Here, we have adopted a comprehensive computational workflow for identification, prioritization and validation of targets from proteomes of Candida albicans and Candida tropicalis. The protocol involves identification of essential drug-target candidates using subtractive genomics, protein-protein interaction network properties and systems biology based methods. The essentiality of the novel metabolic and non-metabolic targets was established by performing in silico gene knockouts, under aerobic as well as anaerobic conditions, and in vitro drug inhibition assays respectively. Deletion of twelve genes that are involved in amino acid, secondary metabolite, and carbon metabolism showed zero growth in metabolic model under simulated conditions. The algorithm, used in this study, can be downloaded from http://pbit.bicnirrh.res.in/offline.php and executed locally.

Visualization and analysis of the interaction network of proteins associated with blood-cell targeting autoimmune diseases

Blood-cell targeting Autoimmune Diseases (BLADs) are complex diseases that affect blood cell formation or prevent blood cell production. Since these clinical conditions are gathering growing attention, experimental approaches are being used to investigate the mechanisms behind their pathogenesis and to identify proteins associated with them. However, computational approaches have not been utilized extensively in the study of BLADs. This study aims to investigate the interaction network of proteins associated with BLADs (BLAD interactome) and to identify novel associations with other human proteins. The method followed in this study combines information regarding protein-protein interaction network properties and autoimmune disease terms. Proteins with high network scores and statistically significant autoimmune disease term enrichment were obtained and 14 of them were designated as candidate proteins associated with BLADs. Additionally, clustering analysis of the BLAD interactome was used and allowed the detection of 17 proteins that act as “connectors” of different BLADs. We expect our findings to further extend experimental efforts for the investigation of the pathogenesis and the relationships of BLADs.

Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease

Identification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We define the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. Using pathway centrality, we identify mediating pathways in three pulmonary diseases (asthma; bronchopulmonary dysplasia (BPD); and chronic obstructive pulmonary disease (COPD)). We systematically evaluate the significance of all identified central pathways using genetic interactions. Mediating pathways shared by all three pulmonary disorders favor innate immune and inflammation-related processes, including toll-like receptor (TLR) signaling, PDGF- and angiotensin-regulated airway remodeling, the JAK-STAT signaling pathway, and interferon gamma. Disease-specific mediators, such as neurodevelopmental processes in BPD or adhesion molecules in COPD, are also highlighted. Some of our findings implicate pathways already in development as drug targets, while others may suggest new therapeutic approaches.

Fusing gene expressions and transitive protein-protein interactions for inference of gene regulatory networks

BackgroundSystematic fusion of multiple data sources for Gene Regulatory Networks (GRN) inference remains a key challenge in systems biology. We incorporate information from protein-protein interaction networks (PPIN) into the process of GRN inference from gene expression (GE) data. However, existing PPIN remain sparse and transitive protein interactions can help predict missing protein interactions. We therefore propose a systematic probabilistic framework on fusing GE data and transitive protein interaction data to coherently build GRN.ResultsWe use a Gaussian Mixture Model (GMM) to soft-cluster GE data, allowing overlapping cluster memberships. Next, a heuristic method is proposed to extend sparse PPIN by incorporating transitive linkages. We then propose a novel way to score extended protein interactions by combining topological properties of PPIN and correlations of GE. Following this, GE data and extended PPIN are fused using a Gaussian Hidden Markov Model (GHMM) in order to identify gene regulatory pathways and refine interaction scores that are then used to constrain the GRN structure. We employ a Bayesian Gaussian Mixture (BGM) model to refine the GRN derived from GE data by using the structural priors derived from GHMM. Experiments on real yeast regulatory networks demonstrate both the feasibility of the extended PPIN in predicting transitive protein interactions and its effectiveness on improving the coverage and accuracy the proposed method of fusing PPIN and GE to build GRN.ConclusionThe GE and PPIN fusion model outperforms both the state-of-the-art single data source models (CLR, GENIE3, TIGRESS) as well as existing fusion models under various constraints.

Function Analysis of Human Protein Interactions Based on a Novel Minimal Loop Algorithm

Background: Various properties of Protein-Protein Interaction (PPI) network have been widely exploited to discover the topological organizing principle and the crucial function motifs involving specific biological pathway or disease process. The current motifs of PPI network are either detected by the topology-based coarse grain algorithms, i.e. community discovering, or depended on the limited-accessible protein annotation data derived precise algorithms. However, the identified network motifs are hardly compatible with the well-defined biological functions according to those two types of methods. Method: In this paper, we proposed a minimal protein loop finding method to explore the elementary structural motifs of human PPI network. Initially, an improved article exchange model was designed to search all the independent shortest protein loops of PPI network. Furthermore, Gene Ontology (GO) based function clustering analysis was implemented to identify the biological functions of the shortest protein loops. Additionally, the disease process associated shortest protein loops were considered as the potential drug targets. </P><P> Result: Our proposed method presents the lowest computational complexity and the highest functional consistency, compared to the three other methods. The functional enrichment and clustering analysis for the identified minimal protein loops revealed the high correlation between the protein loops and the corresponding biological functions, particularly, statistical analysis presenting the protein loops with the length less than 4 is closely connected with some disease process, suggesting the potential drug target. Conclusion: Our minimal protein loop method provides a novel manner to precisely define the functional motif of PPI network, which extends the current knowledge about the cooperating mechanisms and topological properties of protein modules composed of the short loops.

Predicting essential proteins by integrating orthology, gene expressions, and PPI networks.

Identifying essential proteins is very important for understanding the minimal requirements of cellular life and finding human disease genes as well as potential drug targets. Experimental methods for identifying essential proteins are often costly, time-consuming, and laborious. Many computational methods for such task have been proposed based on the topological properties of protein-protein interaction networks (PINs). However, most of these methods have limited prediction accuracy due to the noisy and incomplete natures of PINs and the fact that protein essentiality may relate to multiple biological factors. In this work, we proposed a new centrality measure, OGN, by integrating orthologous information, gene expressions, and PINs together. OGN determines a protein’s essentiality by capturing its co-clustering and co-expression properties, as well as its conservation in the evolution process. The performance of OGN was tested on the species of Saccharomyces cerevisiae. Compared with several published centrality measures, OGN achieves higher prediction accuracy in both working alone and ensemble.

Detecting protein complexes based on a combination of topological and biological properties in protein-protein interaction network.

Protein complexes are known to play a major role in controlling cellular activity in a living being. Identifying complexes from raw protein protein interactions (PPIs) is an important area of research. Earlier work has been limited mostly to yeast. Such protein complex identification methods, when applied to large human PPIs often give poor performance. We introduce a novel method called CSC to detect protein complexes. The method is evaluated in terms of positive predictive value, sensitivity and accuracy using the datasets of the model organism, yeast and humans. CSC outperforms several other competing algorithms for both organisms. Further, we present a framework to establish the usefulness of CSC in analyzing the influence of a given disease gene in a complex topologically as well as biologically considering eight major association factors.

A New Method for Identifying Essential Proteins by Measuring Co-Expression and Functional Similarity.

Identification of essential proteins is a fundamental task for understanding cellular life. With the increasing availability of high-throughput data, which enable the identification of essential proteins by computational methods from the network level. Various computational methods have been proposed based on topological properties of protein-protein interaction (PPI) network or combining additional biological information. However, the prediction precision is still unsatisfied especially when predicting a small amount of essential proteins. In this paper, we propose a novel method for predicting essential proteins by integrating Gene expression profiles and Gene Ontology (GO) annotation data, called GEG. To demonstrate the performance of GEG method, we evaluated GEG on two PPI networks of Saccharomyces cerevisiae. Simulation results showed that GEG achieved better result performance than the five other state-of-the-art methods. We also demonstrate that the GEG is robust against perturbation in terms of precision-recall and receiver operating characteristic measures. The results indicate that appropriate integrating topological properties with additional biological information will be a great help for identification of essential proteins. The new proposed method GEG is effective and useful for predicting essential proteins in PPI networks.

UDoNC: An Algorithm for Identifying Essential Proteins Based on Protein Domains and Protein-Protein Interaction Networks.

Prediction of essential proteins which are crucial to an organism's survival is important for disease analysis and drug design, as well as the understanding of cellular life. The majority of prediction methods infer the possibility of proteins to be essential by using the network topology. However, these methods are limited to the completeness of available protein-protein interaction (PPI) data and depend on the network accuracy. To overcome these limitations, some computational methods have been proposed. However, seldom of them solve this problem by taking consideration of protein domains. In this work, we first analyze the correlation between the essentiality of proteins and their domain features based on data of 13 species. We find that the proteins containing more protein domain types which rarely occur in other proteins tend to be essential. Accordingly, we propose a new prediction method, named UDoNC, by combining the domain features of proteins with their topological properties in PPI network. In UDoNC, the essentiality of proteins is decided by the number and the frequency of their protein domain types, as well as the essentiality of their adjacent edges measured by edge clustering coefficient. The experimental results on S. cerevisiae data show that UDoNC outperforms other existing methods in terms of area under the curve (AUC). Additionally, UDoNC can also perform well in predicting essential proteins on data of E. coli.

Network simulation reveals significant contribution of network motifs to the age-dependency of yeast protein-protein interaction networks.

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

Dynamic protein interaction network construction and applications

With more dynamic information available, researchers' attention has recently shifted from static properties to dynamic properties of protein-protein interaction networks. To compensate the limited ability of technologies of detecting dynamic protein-protein interactions, dynamic protein interaction networks (DPINs) can be constructed by involving proteomic, genomic, and transcriptome analyses. Two groups of DPIN construction methods are classified based on the different focuses on dynamic information extracted from gene expression data. The dynamics of one kind of DPINs is reflected by the changes in protein presence varying with time, while that of the other kind of DPINs is reflected by the differences of coexpression under different conditions. In this review, the applications on DPINs will be discussed, including protein complexes/functional modules and network organization analysis, biomarkers detection in the progression or prognosis of the disease, and network medicine. We also point out the challenges in DPINs construction and future directions in the research of DPINs at the end of this review.

K-Partite cliques of protein interactions: A novel subgraph topology for functional coherence analysis on PPI networks

Many studies are aimed at identifying dense clusters/subgraphs from protein–protein interaction (PPI) networks for protein function prediction. However, the prediction performance based on the dense clusters is actually worse than a simple guilt-by-association method using neighbor counting ideas. This indicates that the local topological structures and properties of PPI networks are still open to new theoretical investigation and empirical exploration. We introduce a novel topological structure called k-partite cliques of protein interactions—a functionally coherent but not-necessarily dense subgraph topology in PPI networks—to study PPI networks. A k-partite protein clique is a maximal k-partite clique comprising two or more nonoverlapping protein subsets between any two of which full interactions are exhibited. In the detection of PPI's maximal k-partite cliques, we propose to transform PPI networks into induced K-partite graphs where edges exist only between the partites. Then, we present a maximal k-partite clique mining (MaCMik) algorithm to enumerate maximal k-partite cliques from K-partite graphs. Our MaCMik algorithm is then applied to a yeast PPI network. We observed interesting and unusually high functional coherence in k-partite protein cliques—the majority of the proteins in k-partite protein cliques, especially those in the same partites, share the same functions, although k-partite protein cliques are not restricted to be dense compared with dense subgraph patterns or (quasi-)cliques. The idea of k-partite protein cliques provides a novel approach of characterizing PPI networks, and so it will help function prediction for unknown proteins.

Predicting potential cancer genes by integrating network properties, sequence features and functional annotations

The discovery of novel cancer genes is one of the main goals in cancer research. Bioinformatics methods can be used to accelerate cancer gene discovery, which may help in the understanding of cancer and the development of drug targets. In this paper, we describe a classifier to predict potential cancer genes that we have developed by integrating multiple biological evidence, including protein-protein interaction network properties, and sequence and functional features. We detected 55 features that were significantly different between cancer genes and non-cancer genes. Fourteen cancer-associated features were chosen to train the classifier. Four machine learning methods, logistic regression, support vector machines (SVMs), BayesNet and decision tree, were explored in the classifier models to distinguish cancer genes from non-cancer genes. The prediction power of the different models was evaluated by 5-fold cross-validation. The area under the receiver operating characteristic curve for logistic regression, SVM, Baysnet and J48 tree models was 0.834, 0.740, 0.800 and 0.782, respectively. Finally, the logistic regression classifier with multiple biological features was applied to the genes in the Entrez database, and 1976 cancer gene candidates were identified. We found that the integrated prediction model performed much better than the models based on the individual biological evidence, and the network and functional features had stronger powers than the sequence features in predicting cancer genes.

A new method for the discovery of essential proteins.

BackgroundExperimental methods for the identification of essential proteins are always costly, time-consuming, and laborious. It is a challenging task to find protein essentiality only through experiments. With the development of high throughput technologies, a vast amount of protein-protein interactions are available, which enable the identification of essential proteins from the network level. Many computational methods for such task have been proposed based on the topological properties of protein-protein interaction (PPI) networks. However, the currently available PPI networks for each species are not complete, i.e. false negatives, and very noisy, i.e. high false positives, network topology-based centrality measures are often very sensitive to such noise. Therefore, exploring robust methods for identifying essential proteins would be of great value.MethodIn this paper, a new essential protein discovery method, named CoEWC (Co-Expression Weighted by Clustering coefficient), has been proposed. CoEWC is based on the integration of the topological properties of PPI network and the co-expression of interacting proteins. The aim of CoEWC is to capture the common features of essential proteins in both date hubs and party hubs. The performance of CoEWC is validated based on the PPI network of Saccharomyces cerevisiae. Experimental results show that CoEWC significantly outperforms the classical centrality measures, and that it also outperforms PeC, a newly proposed essential protein discovery method which outperforms 15 other centrality measures on the PPI network of Saccharomyces cerevisiae. Especially, when predicting no more than 500 proteins, even more than 50% improvements are obtained by CoEWC over degree centrality (DC), a better centrality measure for identifying protein essentiality.ConclusionsWe demonstrate that more robust essential protein discovery method can be developed by integrating the topological properties of PPI network and the co-expression of interacting proteins. The proposed centrality measure, CoEWC, is effective for the discovery of essential proteins.

A kinetic model of the evolution of a protein interaction network

BackgroundKnown protein interaction networks have very particular properties. Old proteins tend to have more interactions than new ones. One of the best statistical representatives of this property is the node degree distribution (distribution of proteins having a given number of interactions). It has previously been shown that this distribution is very close to the sum of two distinct exponential components. In this paper, we asked: What are the possible mechanisms of evolution for such types of networks? To answer this question, we tested a kinetic model for simplified evolution of a protein interactome. Our proposed model considers the emergence of new genes and interactions and the loss of old ones. We assumed that there are generally two coexisting classes of proteins. Proteins constituting the first class are essential only for ecological adaptations and are easily lost when ecological conditions change. Proteins of the second class are essential for basic life processes and, hence, are always effectively protected against deletion. All proteins can transit between the above classes in both directions. We also assumed that the phenomenon of gene duplication is always related to ecological adaptation and that a new copy of a duplicated gene is not essential. According to this model, all proteins gain new interactions with a rate that preferentially increases with the number of interactions (the rich get richer). Proteins can also gain interactions because of duplication. Proteins lose their interactions both with and without the loss of partner genes.ResultsThe proposed model reproduces the main properties of protein-protein interaction networks very well. The connectivity of the oldest part of the interaction network is densest, and the node degree distribution follows the sum of two shifted power-law functions, which is a theoretical generalization of the previous finding. The above distribution covers the wide range of values of node degrees very well, much better than a power law or generalized power law supplemented with an exponential cut-off. The presented model also relates the total number of interactome links to the total number of interacting proteins. The theoretical results were for the interactomes of A. thaliana, B. taurus, C. elegans, D. melanogaster, E. coli, H. pylori, H. sapiens, M. musculus, R. norvegicus and S. cerevisiae.ConclusionsUsing these approaches, the kinetic parameters could be estimated. Finally, the model revealed the evolutionary kinetics of proteome formation, the phenomenon of protein differentiation and the process of gaining new interactions.

Predicting Protein-Protein Interactions Based on PPI Networks

Protein-protein interactions play a key role in the completion of cellular functions and usually correlate to each other in the form of a protein-protein interaction network. In this paper, we propose an algorithm to study the protein- protein interactions using the properties of protein-protein interaction networks. First, the algorithm constructs a protein- protein network according to the two query proteins. All the neighbors of the two query proteins obtained from the online protein databases are also included in the network. Second, the improved network partition algorithm was used to split the network into sub networks. Finally, a scoring function was proposed based on network clusters to predict the protein- protein interactions. The experimental results show that the scoring function based on the PPI network predicts the protein-protein interactions accurately.

Topological Characterization of Protein-Protein Interaction Networks in Human and Mouse

AbstractThe elucidation of the cell's large-scale organization is a primary challenge for post-genomic biology, and understanding the structure and topological properties of protein-protein interaction networks offers an important starting point for such studies. We compare the protein-protein interaction network of the human and mouse, aiming to uncover the network's generic large-scale properties and the impact of the protein's function and cellular localization on the network topology. We show that both human and mouse protein-protein interaction supports a scale-free, topology with hierarchical modularity, indicating that these features represent a robust and generic property of the protein interactions network. We also find strong correlations between the network's structure and the functional role and sub cellular localization of its protein constituents, concluding that most functional and/or localization classes appear as relatively segregated sub networks of the full protein interaction network.

Spectral clustering for detecting protein complexes in protein–protein interaction (PPI) networks

In this paper, we study spectral clustering for detecting protein complexes in PPI (protein–protein interaction) networks, focusing on two open issues: (i) constructing similarity graphs; and (ii) determining the number of clusters. First, we study four similarity graphs to construct graph Laplacian matrices. Then we propose a method to determine the number of clusters based on the properties of PPI networks. Experimental results on PPI networks from DIP data and MIPS data indicate that each similarity graph shows its strengths and disadvantages, and our finding of the number of clusters improves the clustering quality. Finally, spectral clustering obtains results in detecting protein complexes that are comparable to those obtained from several other typical algorithms.

Structure of Protein Interaction Networks and Their Implications on Drug Design

Protein-protein interaction networks (PINs) are rich sources of information that enable the network properties of biological systems to be understood. A study of the topological and statistical properties of budding yeast and human PINs revealed that they are scale-rich and configured as highly optimized tolerance (HOT) networks that are similar to the router-level topology of the Internet. This is different from claims that such networks are scale-free and configured through simple preferential-attachment processes. Further analysis revealed that there are extensive interconnections among middle-degree nodes that form the backbone of the networks. Degree distributions of essential genes, synthetic lethal genes, synthetic sick genes, and human drug-target genes indicate that there are advantageous drug targets among nodes with middle- to low-degree nodes. Such network properties provide the rationale for combinatorial drugs that target less prominent nodes to increase synergetic efficacy and create fewer side effects.

Clustering coefficients of protein-protein interaction networks

The properties of certain networks are determined by hidden variables that are not explicitly measured. The conditional probability (propagator) that a vertex with a given value of the hidden variable is connected to k other vertices determines all measurable properties. We study hidden variable models and find an averaging approximation that enables us to obtain a general analytical result for the propagator. Analytic results showing the validity of the approximation are obtained. We apply hidden variable models to protein-protein interaction networks (PINs) in which the hidden variable is the association free energy, determined by distributions that depend on biochemistry and evolution. We compute degree distributions as well as clustering coefficients of several PINs of different species; good agreement with measured data is obtained. For the human interactome two different parameter sets give the same degree distributions, but the computed clustering coefficients differ by a factor of about 2. This shows that degree distributions are not sufficient to determine the properties of PINs.