Structure Of Protein-protein Interaction Networks Research Articles

Centrality Measures and Their Applications in Network Analysis: Unveiling Important Elements and Their Impact

The applications of centrality measures in protein-protein interaction (PPI) network analysis are diverse and encompass fundamental biological insights; cancer disease-related discoveries, and practical implications for drug development. This multidimensional approach in PPI network analysis provides a comprehensive understanding of the pivotal elements and their impact on biological systems. Analyzing centrality measures in PPI networks enables the identification of essential proteins, hub and bottleneck proteins that occupy strategic positions within the PPI network structure. Essential proteins in PPI networks are significant elements that indicate their importance in maintaining PPI network integrity and functionality. Studying centrality measures can reveal hidden patterns and relationships within these PPI networks. This paper identifes PPI networks with a high degree of connectivity (”hubs”) and proteins with high betweenness centrality (bottlenecks), along with closeness centrality and clustering coefficient. This measure’s significance in PPI networks has implications for various felds. The proposed approach successfully identifed and characterized infuential proteins and found the top 20 essential proteins. These proteins likely hold significant functional importance through hubs and bottlenecks and serve as potential targets for further investigation. This approach has the potential to identify essential proteins involved in cancer diseases. Leveraging centrality measures in the analysis of PPI networks ofers a multifaceted approach to understanding cancer biology and its implications for personalized medicine, drug design, and the development of innovative cancer therapies.

Identifying Protein Complexes With Clear Module Structure Using Pairwise Constraints in Protein Interaction Networks

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.

Compound Target Identification in Tissue-Specific Interaction Networks

Characterizing all possible side effects of compounds is not a trivial task due to unknown off-target proteins that might eventually lead lethal reactions. There is still a tremendous need of computational methods to identify protein targets of a new compound. We have performed a comprehensive analysis for identification of protein targets by integrating tissue-specific protein-protein interaction (PPI) networks and compound induced transcriptome data. Several network centrality metrics are computed to suggest the most probable off-targets of a given compound. The effects of interaction types between proteins and tissue-specific PPI networks are evaluated from multiple perspectives. Usage of network centrality metrics on a tissue-specific PPI network enhances the correct prediction rate of known targets of a given compound. The detailed analysis of successfully identified known targets indicated that degree and local radiality metrics are more practical for determining different types of target protein families, such as GPCR, chemokines, proteasome, and protein kinase families. Therefore, the proposed computational pipeline is applicable while investigating proteins from these families that can be especially targeted for treatment of complex diseases. To the best of our knowledge, this study for the first time presents how tissue-specific transcriptome changes alter the topological structure of PPI networks and the relative effects of tissue-specific networks in target identification. Overall, the proposed computational methods are practical tools for choosing more accurate protein targets for later computational analysis and wet-lab experiments.

A novel method to predict essential proteins based on tensor and HITS algorithm

BackgroundEssential proteins are an important part of the cell and closely related to the life activities of the cell. Hitherto, Protein-Protein Interaction (PPI) networks have been adopted by many computational methods to predict essential proteins. Most of the current approaches focus mainly on the topological structure of PPI networks. However, those methods relying solely on the PPI network have low detection accuracy for essential proteins. Therefore, it is necessary to integrate the PPI network with other biological information to identify essential proteins.ResultsIn this paper, we proposed a novel random walk method for identifying essential proteins, called HEPT. A three-dimensional tensor is constructed first by combining the PPI network of Saccharomyces cerevisiae with multiple biological data such as gene ontology annotations and protein domains. Then, based on the newly constructed tensor, we extended the Hyperlink-Induced Topic Search (HITS) algorithm from a two-dimensional to a three-dimensional tensor model that can be utilized to infer essential proteins. Different from existing state-of-the-art methods, the importance of proteins and the types of interactions will both contribute to the essential protein prediction. To evaluate the performance of our newly proposed HEPT method, proteins are ranked in the descending order based on their ranking scores computed by our method and other competitive methods. After that, a certain number of the ranked proteins are selected as candidates for essential proteins. According to the list of known essential proteins, the number of true essential proteins is used to judge the performance of each method. Experimental results show that our method can achieve better prediction performance in comparison with other nine state-of-the-art methods in identifying essential proteins.ConclusionsThrough analysis and experimental results, it is obvious that HEPT can be used to effectively improve the prediction accuracy of essential proteins by the use of HITS algorithm and the combination of network topology with gene ontology annotations and protein domains, which provides a new insight into multi-data source fusion.

Based on PPI Network and Deep Learning Predicte Protein Function Module Algorithm

The existing Protein protein interaction(PPI) based prediction algorithm for protein functional modules has the disadvantages of low accuracy and less number of functional modules. This paper presents an algorithm based on PPI network and in-depth learning and prediction of protein function module. In this method, three important attributes (node location, PPI network structure and core nodes) are integrated to improve the prediction accuracy and increase the number of protein functional modules. In this paper, First use the Local Density-Based Methods (LDBM) improved density clustering algorithm for clustering analysis. After clustering, use the improved to isometric mapping dimension reduction algorithm for principal component analysis (PPIPCA); then use Multi Layer Perceptron (MLP) for training and function module selection. Last Based on PPI network and deep learning based prediction protein function module algorithm (LPMM) compared with other algorithms. On the basis of yeast dip data set, the accuracy, F value, dimensionality reduction rate and functional module of recognition protein of LPMM algorithm and acc-fmd, MCL and mcode algorithm based on PPI network were compared. Experimental results show that LPMM algorithm is superior to other algorithmsin accuracy, F value, dimensionality reduction rate, number of recognition modules and so on.

Common Neighbors Extension of the Sticky Model for PPI Networks Evaluated by Global and Local Graphlet Similarity.

The structure of protein-protein interaction (PPI) networks has been studied for over a decade. Many theoretical models have been proposed to model PPI network structure, but continuing noise and incompleteness in these networks make conclusions about their structure difficult. Using newer, larger networks from Sept. 2018 BioGRID and Jan. 2019 IID, we show the joint distribution of degree products and common neighbors has a greater impact on PPI edge connectivity than their individual distributions, and introduce two new models (CN and STICKY-CN) for PPI networks employing these features. Since graphlet-based measures are believed to be among the most discerning and sensitive network comparison tools available, we assess their overall global and local fits to PPI networks using Graphlet Kernel (GK). We fit 10 theoretical models to nine BioGRID networks and twelve Integrated Interactive Database (IID) networks and find: (1) STICKY and STICKY-CN are the overall globally best fitting models according to GK, (2) Hyperbolic Geometric Graph model is a better fit than any STICKY-based model on 4 species, (3) though STICKY-CN provides a better local fit than the STICKY model, the CN model provides the greatest local fit over most species. We conclude that the inclusion of CN into STICKY-CN makes it the best overall fit for PPI networks as it is a good fit locally and globally.

Viewing the Meso-Scale Structures in Protein-Protein Interaction Networks Using 2-Clubs

Many current analyses on protein-protein interaction (PPI) networks concentrate on developing the algorithms for identifying the functional modules within the PPI networks. However, understanding the internal structure in the functional modules is needed to define their roles within the entire network. We propose the use of a two-club meso-scale structure that possesses refined inner topological structural properties, useful for deciphering the aforementioned obscure structural supporting evidences. In this paper, we: 1) illustrate the feasibility and advantages of modeling functional modules as two-clubs in PPI networks by taking statistics on the diameter distribution of benchmark functional modules within several golden standard sets; 2) categorize the two-clubs into six subcategories through the use of well-defined internal graph-theoretic characterizations; and 3) analyze these six subcategories based on factors, such as their structure, and various metrics, such as topological centralities, the numbers of involved transcription factors and essential genes, and the numbers of matched protein complexes or GO terms. Our structure-driven analysis allows us to predict the roles of identified functional modules from their network structure alone. Our subcategories of coteries and social circles serve as a classification scheme for determining which functional modules are central, regional, and satellite and which are coordinating. Experimental results show that in order to precisely control and examine the PPI networks for further research, a clear understanding of how the internal topology of modules affects their function is essential.

Identification of genes related to proliferative diabetic retinopathy through RWR algorithm based on protein–protein interaction network

Proliferative diabetic retinopathy (PDR) is one of the most common complications of diabetes and can lead to blindness. Proteomic studies have provided insight into the pathogenesis of PDR and a series of PDR-related genes has been identified but are far from fully characterized because the experimental methods are expensive and time consuming. In our previous study, we successfully identified 35 candidate PDR-related genes through the shortest-path algorithm. In the current study, we developed a computational method using the random walk with restart (RWR) algorithm and the protein–protein interaction (PPI) network to identify potential PDR-related genes. After some possible genes were obtained by the RWR algorithm, a three-stage filtration strategy, which includes the permutation test, interaction test and enrichment test, was applied to exclude potential false positives caused by the structure of PPI network, the poor interaction strength, and the limited similarity on gene ontology (GO) terms and biological pathways. As a result, 36 candidate genes were discovered by the method which was different from the 35 genes reported in our previous study. A literature review showed that 21 of these 36 genes are supported by previous experiments. These findings suggest the robustness and complementary effects of both our efforts using different computational methods, thus providing an alternative method to study PDR pathogenesis.

Predicting colorectal cancer recurrence by utilizing multiple-view multiple-learner supervised learning.

635 Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality in the United States. A key therapeutic dilemma in the treatment of CRC is whether patients with stage II and stage III disease require adjuvant chemotherapy after surgical resection. Attempts to improve identification of patients at increased risk of recurrence have yielded many predictive models based on gene expression data, but none are FDA approved and none are used in standard clinical practice. To improve recurrence prediction, we utilize a machine learning approach to predict recurrence status at 3 years after diagnosis. Methods: A dataset was curated from six publically available microarray datasets, and multiple views were generated to include information from non-tumor tissue gene expression patterns, gene set structure, protein-protein interaction network structure, previously curated molecular signatures, and identified tumor suppressor/driver mutations. These views were used to train a diverse pool of base learners using 10x 10-fold cross-validation. Stacked generalization was used to train an ensemble model, also known as a meta-learner, from the predictions of these base learners. Results: The performance of microarray trained models was significantly better compared to models trained on clinical data (Paired Wilcoxon signed rank test, p = 1.49 x 10-8), demonstrating that molecular data predicts recurrence significantly better than basic clinical data. Review of the model training performances revealed that non-linear classifiers often outperform linear classifiers, and that ensemble methods can also enhance performance. We also demonstrate the feasibility of the multiple-view multiple learner (MVML) supervised learning framework to generate and integrate predictions across a diverse set of learners, with the performance of the meta-learner exceeding or matching that of the best base learners across all performance metrics. Conclusions: This work represents the first effort to use ensemble learning to predict CRC recurrence and highlights the promise of ensemble learning to improve the performance of predictive models in order to realize the goals of precision medicine.

The Intrinsic Geometric Structure of Protein-Protein Interaction Networks for Protein Interaction Prediction.

Recent developments in high-throughput technologies for measuring protein-protein interaction (PPI) have profoundly advanced our ability to systematically infer protein function and regulation. However, inherently high false positive and false negative rates in measurement have posed great challenges in computational approaches for the prediction of PPI. A good PPI predictor should be 1) resistant to high rate of missing and spurious PPIs, and 2) robust against incompleteness of observed PPI networks. To predict PPI in a network, we developed an intrinsic geometry structure (IGS) for network, which exploits the intrinsic and hidden relationship among proteins in network through a heat diffusion process. In this process, all explicit PPIs participate simultaneously to glue local infinitesimal and noisy experimental interaction data to generate a global macroscopic descriptions about relationships among proteins. The revealed implicit relationship can be interpreted as the probability of two proteins interacting with each other. The revealed relationship is intrinsic and robust against individual, local and explicit protein interactions in the original network. We apply our approach to publicly available PPI network data for the evaluation of the performance of PPI prediction. Experimental results indicate that, under different levels of the missing and spurious PPIs, IGS is able to robustly exploit the intrinsic and hidden relationship for PPI prediction with a higher sensitivity and specificity compared to that of recently proposed methods.

Mining topological structures of protein-protein interaction networks for human brain-specific genes.

Compared to other placental mammals, humans have unique thinking and cognitive abilities because of their developed cerebral cortex composed of billions of neurons and synaptic connections. As the primary effectors of the mechanisms of life, proteins and their interactions form the basis of cellular and molecular functions in the living body. In this paper, we developed a pipeline for mining topological structures, identifying functional modules, and analyzing their functions from publically available datasets. A human brain-specific protein-protein interaction network with 1482 nodes and 3105 edges was built using a MapReduce based shortest path algorithm. Within this, 7 functional cliques were identified using a network clustering method, 98 hub proteins were obtained by the calculation of betweenness and connectivity, and 5 closest relationship to clique connector proteins were recognized by the combination scores of topological distance and gene ontology similarity. Furthermore, we discovered functional modules interacting with TP53 protein, which involves several fragmented research study conclusions and might be an important clue for further in vivo or in silico experiments to confirm these associations.

TEMPI: probabilistic modeling time-evolving differential PPI networks with multiPle information.

Motivation: Time-evolving differential protein–protein interaction (PPI) networks are essential to understand serial activation of differentially regulated (up- or downregulated) cellular processes (DRPs) and their interplays over time. Despite developments in the network inference, current methods are still limited in identifying temporal transition of structures of PPI networks, DRPs associated with the structural transition and the interplays among the DRPs over time.Results: Here, we present a probabilistic model for estimating Time-Evolving differential PPI networks with MultiPle Information (TEMPI). This model describes probabilistic relationships among network structures, time-course gene expression data and Gene Ontology biological processes (GOBPs). By maximizing the likelihood of the probabilistic model, TEMPI estimates jointly the time-evolving differential PPI networks (TDNs) describing temporal transition of PPI network structures together with serial activation of DRPs associated with transiting networks. This joint estimation enables us to interpret the TDNs in terms of temporal transition of the DRPs. To demonstrate the utility of TEMPI, we applied it to two time-course datasets. TEMPI identified the TDNs that correctly delineated temporal transition of DRPs and time-dependent associations between the DRPs. These TDNs provide hypotheses for mechanisms underlying serial activation of key DRPs and their temporal associations.Availability and implementation: Source code and sample data files are available at http://sbm.postech.ac.kr/tempi/sources.zip.Contact: seungjin@postech.ac.kr or dhwang@dgist.ac.krSupplementary information: Supplementary data are available at Bioinformatics online.

Protein–protein interaction network analysis and gene set enrichment analysis in epilepsy patients with brain cancer

Many patients with brain cancer experience seizures or epilepsy and tumor-associated epilepsy (TAE) significantly decreases their quality of life. This study aimed to achieve a better understanding of the mechanisms of TAE. The differentially expressed genes (DEG) between epilepsy patients with or without brain tumor were firstly screened using the Linear Models for Microarray Data package using GSE4290 datasets from the USA National Center for Biotechnology Information Gene Expression Omnibus database. Then the protein-protein interaction (PPI) network, using data from the Human Protein Reference Database and the Biological General Repository for Interaction Datasets, was constructed. For further analysis, the PPI network structure and clusters in this PPI network were identified by ClusterOne. Meanwhile, gene set enrichment analysis was performed to illuminate the biological pathways and processes which generally affect patients with TAE. A total of 5113 DEG were identified and a PPI network, which contained 114 DEG and 21 normal genes, was established. Proteins, which mainly belonged to the mini chromosome maintenance and collagen families, were discovered to be enriched in the three identified clusters in the PPI network. Finally, several biological pathways (including cell cycle, DNA replication and transforming growth factor β1 signaling pathways) and processes (such as nucleocytoplasmic transport, nuclear transport and regulation of phosphorylation) were identified. Proteins in these three clusters may become new targets for TAE treatment. Our results provide some potential underlying biomarkers for understanding the pathogenesis of epilepsy in patients with brain tumor.

Identifying Protein Complexes Based on Multiple Topological Structures in PPI Networks

Various computational algorithms are developed to identify protein complexes based on only one of specific topological structures in protein-protein interaction (PPI) networks, such as cliques, dense subgraphs, core-attachment structures and starlike structures. However, protein complexes exhibit intricate connections in a PPI network. They cannot be fully detected by only single topological structure. In this paper, we propose an algorithm based on multiple topological structures to identify protein complexes from PPI networks. In the proposed algorithm, four single topological structure based algorithms are first employed to identify raw predictions with specific topological structures, respectively. Those raw predictions are trimmed according to their topological information or GO annotations. Similar results are carefully merged before generating final predictions. Numerical experiments are conducted on a yeast PPI network of DIP and a human PPI network of HPRD. The predicted results show that the multiple topological structure based algorithm can not only obtain a more number of predictions, but also generate results with high accuracy in terms of f-score, matching with known protein complexes and functional enrichments with GO.

Construction of Ontology Augmented Networks for Protein Complex Prediction

Protein complexes are of great importance in understanding the principles of cellular organization and function. The increase in available protein-protein interaction data, gene ontology and other resources make it possible to develop computational methods for protein complex prediction. Most existing methods focus mainly on the topological structure of protein-protein interaction networks, and largely ignore the gene ontology annotation information. In this article, we constructed ontology augmented networks with protein-protein interaction data and gene ontology, which effectively unified the topological structure of protein-protein interaction networks and the similarity of gene ontology annotations into unified distance measures. After constructing ontology augmented networks, a novel method (clustering based on ontology augmented networks) was proposed to predict protein complexes, which was capable of taking into account the topological structure of the protein-protein interaction network, as well as the similarity of gene ontology annotations. Our method was applied to two different yeast protein-protein interaction datasets and predicted many well-known complexes. The experimental results showed that (i) ontology augmented networks and the unified distance measure can effectively combine the structure closeness and gene ontology annotation similarity; (ii) our method is valuable in predicting protein complexes and has higher F1 and accuracy compared to other competing methods.

A New Integration-Centric Algorithm of Identifying Essential Proteins Based on Topology Structure of Protein-Protein Interaction Network and Complex Information

Essential proteins are necessary for the survival and development of organism. Many computational approaches have been proposed for predicting essential proteins based on protein-protein interaction (PPI) network. In this paper, we propose a new centrality algorithm for identifying essential proteins, named CSC algorithm. CSC algorithm integrates topology character of PPI network and in-degree of proteins in complexes. We use CSC algorithm to identify the essential proteins in PPI network of Saccharomyces cerevisiae. The results show that the ratio of identified essential proteins on CSC algorithm is higher than other ten centrality methods: Degree Centrality (DC), Betweenness Centrality (BC), Closeness Centrality (CC), Subgraph Centrality (SC), Eigenvector Centrality (EC), Information Centrality (IC), Bottle Neck (BN), Local Average Connectivity-based method (LAC), Sum of ECC (SoECC) and PeC. Particularly, the identification accuracy of CSC algorithm is more than 40% over the six classic centrality measures (DC, BC, CC, SC, EC, IC). Keywords: Centrality measures, clustering coefficient, essential proteins, protein-protein interaction, protein complex, topology.

Protein Complex Prediction in Large Ontology Attributed Protein-Protein Interaction Networks

Protein complexes are important for unraveling the secrets of cellular organization and function. Many computational approaches have been developed to predict protein complexes in protein-protein interaction (PPI) networks. However, most existing approaches focus mainly on the topological structure of PPI networks, and largely ignore the gene ontology (GO) annotation information. In this paper, we constructed ontology attributed PPI networks with PPI data and GO resource. After constructing ontology attributed networks, we proposed a novel approach called CSO (clustering based on network structure and ontology attribute similarity). Structural information and GO attribute information are complementary in ontology attributed networks. CSO can effectively take advantage of the correlation between frequent GO annotation sets and the dense subgraph for protein complex prediction. Our proposed CSO approach was applied to four different yeast PPI data sets and predicted many well-known protein complexes. The experimental results showed that CSO was valuable in predicting protein complexes and achieved state-of-the-art performance.

The evolutionary dynamics of protein-protein interaction networks inferred from the reconstruction of ancient networks.

Cellular functions are based on the complex interplay of proteins, therefore the structure and dynamics of these protein-protein interaction (PPI) networks are the key to the functional understanding of cells. In the last years, large-scale PPI networks of several model organisms were investigated. A number of theoretical models have been developed to explain both the network formation and the current structure. Favored are models based on duplication and divergence of genes, as they most closely represent the biological foundation of network evolution. However, studies are often based on simulated instead of empirical data or they cover only single organisms. Methodological improvements now allow the analysis of PPI networks of multiple organisms simultaneously as well as the direct modeling of ancestral networks. This provides the opportunity to challenge existing assumptions on network evolution. We utilized present-day PPI networks from integrated datasets of seven model organisms and developed a theoretical and bioinformatic framework for studying the evolutionary dynamics of PPI networks. A novel filtering approach using percolation analysis was developed to remove low confidence interactions based on topological constraints. We then reconstructed the ancient PPI networks of different ancestors, for which the ancestral proteomes, as well as the ancestral interactions, were inferred. Ancestral proteins were reconstructed using orthologous groups on different evolutionary levels. A stochastic approach, using the duplication-divergence model, was developed for estimating the probabilities of ancient interactions from today's PPI networks. The growth rates for nodes, edges, sizes and modularities of the networks indicate multiplicative growth and are consistent with the results from independent static analysis. Our results support the duplication-divergence model of evolution and indicate fractality and multiplicative growth as general properties of the PPI network structure and dynamics.

Choosing appropriate models for protein–protein interaction networks: a comparison study

With the increase of available protein-protein interaction (PPI) data, more and more efforts have been put to PPI network modeling, and a number of models of PPI networks have been proposed. Roughly speaking, good models of PPI networks should be able to accurately describe PPI mechanisms, and thus reproduce the structures of PPI networks. With such models, theoretical and/or computational biologists can efficiently explore the evolution and dynamics of PPI networks. However, a theoretical and/or computational biologist may feel confused when she/he has to choose a proper PPI model for her/his research work from a dozen of candidate models, while there is no guideline available to help her/him. To tackle this problem, in this article, we carry out a comprehensive performance comparison study on 12 existing models over PPI datasets of four species (yeast, mouse, fruit fly and nematode), by comparing the global and local statistical properties of the original PPI networks and the model-reproduced ones. To draw more convincing conclusions, we use the mean reciprocal rank to combine the ranks of a certain model on all statistical properties. Our experimental results indicate that the PS_Seed model [Solé and Pastor-Satorras (PS) model with seed] the STICKY model and the DD_Seed model (Duplication-Divergence model with seed) fit best with the test PPI datasets. By analyzing the underlying mechanisms of the models with better fitting ability, our analysis shows that the evolutionary mechanism of node duplication and link dynamics and the mechanisms with 'degree-weighted' behaviors seem to be able to describe the PPI networks better.

An Overview of the Statistical Methods Used for Inferring Gene Regulatory Networks and Protein-Protein Interaction Networks

The large influx of data from high-throughput genomic and proteomic technologies has encouraged the researchers to seek approaches for understanding the structure of gene regulatory networks and proteomic networks. This work reviews some of the most important statistical methods used for modeling of gene regulatory networks (GRNs) and protein-protein interaction (PPI) networks. The paper focuses on the recent advances in the statistical graphical modeling techniques, state-space representation models, and information theoretic methods that were proposed for inferring the topology of GRNs. It appears that the problem of inferring the structure of PPI networks is quite different from that of GRNs. Clustering and probabilistic graphical modeling techniques are of prime importance in the statistical inference of PPI networks, and some of the recent approaches using these techniques are also reviewed in this paper. Performance evaluation criteria for the approaches used for modeling GRNs and PPI networks are also discussed.