Showing papers on "Interaction network published in 2015"

The Roles of Post-translational Modifications in the Context of Protein Interaction Networks

Abstract: Among other effects, post-translational modifications (PTMs) have been shown to exert their function via the modulation of protein-protein interactions. For twelve different main PTM-types and associated subtypes and across 9 diverse species, we investigated whether particular PTM-types are associated with proteins with specific and possibly “strategic” placements in the network of all protein interactions by determining informative network-theoretic properties. Proteins undergoing a PTM were observed to engage in more interactions and positioned in more central locations than non-PTM proteins. Among the twelve considered PTM-types, phosphorylated proteins were identified most consistently as being situated in central network locations and with the broadest interaction spectrum to proteins carrying other PTM-types, while glycosylated proteins are preferentially located at the network periphery. For the human interactome, proteins undergoing sumoylation or proteolytic cleavage were found with the most characteristic network properties. PTM-type-specific protein interaction network (PIN) properties can be rationalized with regard to the function of the respective PTM-carrying proteins. For example, glycosylation sites were found enriched in proteins with plasma membrane localizations and transporter or receptor activity, which generally have fewer interacting partners. The involvement in disease processes of human proteins undergoing PTMs was also found associated with characteristic PIN properties. By integrating global protein interaction networks and specific PTMs, our study offers a novel approach to unraveling the role of PTMs in cellular processes.

Fundamentals of protein interaction network mapping

Abstract: Studying protein interaction networks of all proteins in an organism ("interactomes") remains one of the major challenges in modern biomedicine. Such information is crucial to understanding cellular pathways and developing effective therapies for the treatment of human diseases. Over the past two decades, diverse biochemical, genetic, and cell biological methods have been developed to map interactomes. In this review, we highlight basic principles of interactome mapping. Specifically, we discuss the strengths and weaknesses of individual assays, how to select a method appropriate for the problem being studied, and provide general guidelines for carrying out the necessary follow-up analyses. In addition, we discuss computational methods to predict, map, and visualize interactomes, and provide a summary of some of the most important interactome resources. We hope that this review serves as both a useful overview of the field and a guide to help more scientists actively employ these powerful approaches in their research.

An Interaction Model for Simulation and Mitigation of Cascading Failures

Abstract: In this paper, the interactions between component failures are quantified and the interaction matrix and interaction network are obtained. The quantified interactions can capture the general propagation patterns of the cascades from utilities or simulation, thus helping to better understand how cascading failures propagate and to identify key links and key components that are crucial for cascading failure propagation. By utilizing these interactions a high-level probabilistic model called interaction model is proposed to study the influence of interactions on cascading failure risk and to support online decision-making. It is much more time-efficient to first quantify the interactions between component failures with fewer original cascades from a more detailed cascading failure model and then perform the interaction model simulation than it is to directly simulate a large number of cascades with a more detailed model. Interaction-based mitigation measures are suggested to mitigate cascading failure risk by weakening key links, which can be achieved in real systems by wide-area protection such as blocking of some specific protective relays. The proposed interaction quantifying method and interaction model are validated with line outage data generated by the AC OPA cascading simulations on the IEEE 118-bus system.

Drug target prioritization by perturbed gene expression and network information.

Abstract: Drugs bind to their target proteins, which interact with downstream effectors and ultimately perturb the transcriptome of a cancer cell. These perturbations reveal information about their source, i.e., drugs' targets. Here, we investigate whether these perturbations and protein interaction networks can uncover drug targets and key pathways. We performed the first systematic analysis of over 500 drugs from the Connectivity Map. First, we show that the gene expression of drug targets is usually not significantly affected by the drug perturbation. Hence, expression changes after drug treatment on their own are not sufficient to identify drug targets. However, ranking of candidate drug targets by network topological measures prioritizes the targets. We introduce a novel measure, local radiality, which combines perturbed genes and functional interaction network information. The new measure outperforms other methods in target prioritization and proposes cancer-specific pathways from drugs to affected genes for the first time. Local radiality identifies more diverse targets with fewer neighbors and possibly less side effects.

ComPPI: a cellular compartment-specific database for protein-protein interaction network analysis.

Abstract: Here we present ComPPI, a cellular compartment-specific database of proteins and their interactions enabling an extensive, compartmentalized protein–protein interaction network analysis (URL: http://ComPPI.LinkGroup.hu). ComPPI enables the user to filter biologically unlikely interactions, where the two interacting proteins have no common subcellular localizations and to predict novel properties, such as compartment-specific biological functions. ComPPI is an integrated database covering four species (S. cerevisiae, C. elegans, D. melanogaster and H. sapiens). The compilation of nine protein–protein interaction and eight subcellular localization data sets had four curation steps including a manually built, comprehensive hierarchical structure of >1600 subcellular localizations. ComPPI provides confidence scores for protein subcellular localizations and protein–protein interactions. ComPPI has user-friendly search options for individual proteins giving their subcellular localization, their interactions and the likelihood of their interactions considering the subcellular localization of their interacting partners. Download options of search results, whole-proteomes, organelle-specific interactomes and subcellular localization data are available on its website. Due to its novel features, ComPPI is useful for the analysis of experimental results in biochemistry and molecular biology, as well as for proteome-wide studies in bioinformatics and network science helping cellular biology, medicine and drug design.

Topology-function conservation in protein–protein interaction networks

Abstract: Motivation: Proteins underlay the functioning of a cell and the wiring of proteins in protein–protein interaction network (PIN) relates to their biological functions. Proteins with similar wiring in the PIN (topology around them) have been shown to have similar functions. This property has been successfully exploited for predicting protein functions. Topological similarity is also used to guide network alignment algorithms that find similarly wired proteins between PINs of different species; these similarities are used to transfer annotation across PINs, e.g. from model organisms to human. To refine these functional predictions and annotation transfers, we need to gain insight into the variability of the topology-function relationships. For example, a function may be significantly associated with specific topologies, while another function may be weakly associated with several different topologies. Also, the topology-function relationships may differ between different species. Results: To improve our understanding of topology-function relationships and of their conservation among species, we develop a statistical framework that is built upon canonical correlation analysis. Using the graphlet degrees to represent the wiring around proteins in PINs and gene ontology (GO) annotations to describe their functions, our framework: (i) characterizes statistically significant topology-function relationships in a given species, and (ii) uncovers the functions that have conserved topology in PINs of different species, which we term topologically orthologous functions. We apply our framework to PINs of yeast and human, identifying seven biological process and two cellular component GO terms to be topologically orthologous for the two organisms. Availability and implementation: http://bio-nets.doc.ic.ac.uk/goCCA.zip Contact: ku.ca.lairepmi@ahsatan Supplementary information: Supplementary data are available at Bioinformatics online.

Effect of localization on the stability of mutualistic ecological networks.

Abstract: The relationships between the core-periphery architecture of the species interaction network and the mechanisms ensuring the stability in mutualistic ecological communities are still unclear. In particular, most studies have focused their attention on asymptotic resilience or persistence, neglecting how perturbations propagate through the system. Here we develop a theoretical framework to evaluate the relationship between the architecture of the interaction networks and the impact of perturbations by studying localization, a measure describing the ability of the perturbation to propagate through the network. We show that mutualistic ecological communities are localized, and localization reduces perturbation propagation and attenuates its impact on species abundance. Localization depends on the topology of the interaction networks, and it positively correlates with the variance of the weighted degree distribution, a signature of the network topological heterogeneity. Our results provide a different perspective on the interplay between the architecture of interaction networks in mutualistic communities and their stability.

Identification of Essential Proteins Based on a New Combination of Local Interaction Density and Protein Complexes.

Abstract: Background Computational approaches aided by computer science have been used to predict essential proteins and are faster than expensive, time-consuming, laborious experimental approaches. However, the performance of such approaches is still poor, making practical applications of computational approaches difficult in some fields. Hence, the development of more suitable and efficient computing methods is necessary for identification of essential proteins. Method In this paper, we propose a new method for predicting essential proteins in a protein interaction network, local interaction density combined with protein complexes (LIDC), based on statistical analyses of essential proteins and protein complexes. First, we introduce a new local topological centrality, local interaction density (LID), of the yeast PPI network; second, we discuss a new integration strategy for multiple bioinformatics. The LIDC method was then developed through a combination of LID and protein complex information based on our new integration strategy. The purpose of LIDC is discovery of important features of essential proteins with their neighbors in real protein complexes, thereby improving the efficiency of identification. Results Experimental results based on three different PPI(protein-protein interaction) networks of Saccharomyces cerevisiae and Escherichia coli showed that LIDC outperformed classical topological centrality measures and some recent combinational methods. Moreover, when predicting MIPS datasets, the better improvement of performance obtained by LIDC is over all nine reference methods (i.e., DC, BC, NC, LID, PeC, CoEWC, WDC, ION, and UC). Conclusions LIDC is more effective for the prediction of essential proteins than other recently developed methods.

Predicting Long Noncoding RNA and Protein Interactions Using Heterogeneous Network Model

Abstract: Recent study shows that long noncoding RNAs (lncRNAs) are participating in diverse biological processes and complex diseases. However, at present the functions of lncRNAs are still rarely known. In this study, we propose a network-based computational method, which is called lncRNA-protein interaction prediction based on Heterogeneous Network Model (LPIHN), to predict the potential lncRNA-protein interactions. First, we construct a heterogeneous network by integrating the lncRNA-lncRNA similarity network, lncRNA-protein interaction network, and protein-protein interaction (PPI) network. Then, a random walk with restart is implemented on the heterogeneous network to infer novel lncRNA-protein interactions. The leave-one-out cross validation test shows that our approach can achieve an AUC value of 96.0%. Some lncRNA-protein interactions predicted by our method have been confirmed in recent research or database, indicating the efficiency of LPIHN to predict novel lncRNA-protein interactions.

Extensive site-directed mutagenesis reveals interconnected functional units in the alkaline phosphatase active site

Abstract: Enzymes enable life by accelerating reaction rates to biological timescales. Conventional studies have focused on identifying the residues that have a direct involvement in an enzymatic reaction, but these so-called 'catalytic residues' are embedded in extensive interaction networks. Although fundamental to our understanding of enzyme function, evolution, and engineering, the properties of these networks have yet to be quantitatively and systematically explored. We dissected an interaction network of five residues in the active site of Escherichia coli alkaline phosphatase. Analysis of the complex catalytic interdependence of specific residues identified three energetically independent but structurally interconnected functional units with distinct modes of cooperativity. From an evolutionary perspective, this network is orders of magnitude more probable to arise than a fully cooperative network. From a functional perspective, new catalytic insights emerge. Further, such comprehensive energetic characterization will be necessary to benchmark the algorithms required to rationally engineer highly efficient enzymes.

Computational prediction of molecular pathogen-host interactions based on dual transcriptome data

Abstract: Inference of inter-species gene regulatory networks based on gene expression data is an important computational method to predict pathogen-host interactions (PHIs). Both the experimental setup and the nature of PHIs exhibit certain characteristics. First, besides an environmental change, the battle between pathogen and host leads to a constantly changing environment and thus complex gene expression patterns. Second, there might be a delay until one of the organisms reacts. Third, toward later time points only one organism may survive leading to missing gene expression data of the other organism. Here, we account for PHI characteristics by extending NetGenerator, a network inference tool that predicts gene regulatory networks from gene expression time series data. We tested multiple modeling scenarios regarding the stimuli functions of the interaction network based on a benchmark example. We show that modeling perturbation of a PHI network by multiple stimuli better represents the underlying biological phenomena. Furthermore, we utilized the benchmark example to test the influence of missing data points on the inference performance. Our results suggest that PHI network inference with missing data is possible, but we recommend to provide complete time series data. Finally, we extended the NetGenerator tool to incorporate gene- and time point specific variances, because complex PHIs may lead to high variance in expression data. Sample variances are directly considered in the objective function of NetGenerator and indirectly by testing the robustness of interactions based on variance dependent disturbance of gene expression values. We evaluated the method of variance incorporation on dual RNA sequencing (RNA-Seq) data of Mus musculus dendritic cells incubated with Candida albicans and proofed our method by predicting previously verified PHIs as robust interactions.

Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex

Abstract: The three dimensional conformation of the genome in the cell nucleus influences important biological processes such as gene expression regulation. Recent studies have shown a strong correlation between chromatin interactions and gene co-expression. However, predicting gene co-expression from frequent long-range chromatin interactions remains challenging. We address this by characterizing the topology of the cortical chromatin interaction network using scale-aware topological measures. We demonstrate that based on these characterizations it is possible to accurately predict spatial co-expression between genes in the mouse cortex. Consistent with previous findings, we find that the chromatin interaction profile of a gene-pair is a good predictor of their spatial co-expression. However, the accuracy of the prediction can be substantially improved when chromatin interactions are described using scale-aware topological measures of the multi-resolution chromatin interaction network. We conclude that, for co-expression prediction, it is necessary to take into account different levels of chromatin interactions ranging from direct interaction between genes (i.e. small-scale) to chromatin compartment interactions (i.e. large-scale).

Distributed adaptive control for synchronization in directed complex networks

Abstract: The dynamics of a complex network is generally very complicated due to the self-dynamics of the node and their interactions. Many existing conditions for reaching certain desirable dynamics in a complex network require global information of the network, for example, the spectrum of its Laplacian matrix. A challenging problem is how the network structure affects the network dynamics in a distributed way especially for directed networks, which is still unclear today. This paper investigates the impact of the network structure on a general directed complex network and develops a scheme to change the weights in a local manner to achieve a desired behavior. In particular, network synchronization is investigated, for which some distributed adaptive laws are designed on the coupling weights for reaching synchronization in a directed complex network. It is found that the directed spanning tree structure is helpful while the aggregation and circular structures are harmful for achieving network synchronization. It ...

Increased signaling entropy in cancer requires the scale-free property of protein interaction networks

Abstract: One of the key characteristics of cancer cells is an increased phenotypic plasticity, driven by underlying genetic and epigenetic perturbations. However, at a systems-level it is unclear how these perturbations give rise to the observed increased plasticity. Elucidating such systems-level principles is key for an improved understanding of cancer. Recently, it has been shown that signaling entropy, an overall measure of signaling pathway promiscuity, and computable from integrating a sample's gene expression profile with a protein interaction network, correlates with phenotypic plasticity and is increased in cancer compared to normal tissue. Here we develop a computational framework for studying the effects of network perturbations on signaling entropy. We demonstrate that the increased signaling entropy of cancer is driven by two factors: (i) the scale-free (or near scale-free) topology of the interaction network, and (ii) a subtle positive correlation between differential gene expression and node connectivity. Indeed, we show that if protein interaction networks were random graphs, described by Poisson degree distributions, that cancer would generally not exhibit an increased signaling entropy. In summary, this work exposes a deep connection between cancer, signaling entropy and interaction network topology.

miRNA–mRNA Interaction Network in Non-small Cell Lung Cancer

Abstract: MicroRNAs (miRNAs) are small RNA molecules, about 20-25 nucleotides in length. They repress or degrade messenger RNA (mRNA) translation, which are involved in human cancer. In this study based on paired miRNA and mRNA expression profiles of non-small cell lung cancer samples, we constructed and analyzed miRNA-mRNA interaction network via several bioinformatics softwares and platforms. This integrative network is comprised of 249 nodes for mRNA, 90 nodes for miRNA and 290 edges that show regulations between target genes and miRNAs. The three miR-1207-5p, miR-1228* and miR-939 are the most connected miRNA that regulated a large number of genes. ST8SIA2, MED1 and HDAC4, SPN, which are targeted by multiple miRNAs and located in the center of the network, are involved in both lung cancer and nervous system via functional annotation analysis. Such a global interaction network of miRNA-mRNA in lung cancer will contribute to refining miRNA target predictions and developing novel therapeutic candidates.

Persistent variation in spatial behavior affects the structure and function of interaction networks

Abstract: The function of a network is affected by its structure. For example, the presence of highly interactive individuals, or hubs, influences the extent and rate of information spread across a network. In a network of interactions, the duration over which individual variation in interactions persists may affect how the network operates. Individuals may persist in their behavior over time and across situations, often referred to as personality. Colonies of social insects are an example of a biological system in which the structure of the coordinated networks of interacting workers may greatly influence information flow within the colony, and therefore its collective behavior. Here I investigate the effects of persistence in walking patterns on interaction networks us- ing computer simulations that are parameterized using observed behavior of harvester ants. I examine how the duration of persis- tence in spatial behavior influences network structure. Furthermore, I explore how spatial features of the environment affect the relationship between persistent behavior and network structure. I show that as persistence increases, the skewness of the weighted degree distribution of the interaction network increases. However, this relationship holds only when ants are confined in a space with boundaries, but not when physical barriers are absent. These findings suggest that the influence of animal personalities on network structure and function depends on the environment in which the animals reside (Current Zoology 61 (1): 98-106, 2015).

Improving the robustness of complex networks with preserving community structure.

Abstract: Complex networks are everywhere, such as the power grid network, the airline network, the protein-protein interaction network, and the road network. The networks are ‘robust yet fragile’, which means that the networks are robust against random failures but fragile under malicious attacks. The cascading failures, system-wide disasters and intentional attacks on these networks are deserving of in-depth study. Researchers have proposed many solutions to improve the robustness of these networks. However whilst many solutions preserve the degree distribution of the networks, little attention is paid to the community structure of these networks. We argue that the community structure of a network is a defining characteristic of a network which identifies its functionality and thus should be preserved. In this paper, we discuss the relationship between robustness and the community structure. Then we propose a 3-step strategy to improve the robustness of a network, while retaining its community structure, and also its degree distribution. With extensive experimentation on representative real-world networks, we demonstrate that our method is effective and can greatly improve the robustness of networks, while preserving community structure and degree distribution. Finally, we give a description of a robust network, which is useful not only for improving robustness, but also for designing robust networks and integrating networks.

MyProteinNet: build up-to-date protein interaction networks for organisms, tissues and user-defined contexts

Abstract: The identification of the molecular pathways active in specific contexts, such as disease states or drug responses, often requires an extensive view of the potential interactions between a subset of proteins. This view is not easily obtained: it requires the integration of context-specific protein list or expression data with up-to-date data of protein interactions that are typically spread across multiple databases. The MyProteinNet web server allows users to easily create such context-sensitive protein interaction networks. Users can automatically gather and consolidate data from up to 11 different databases to create a generic protein interaction network (interactome). They can score the interactions based on reliability and filter them by user-defined contexts including molecular expression and protein annotation. The output of MyProteinNet includes the generic and filtered interactome files, together with a summary of their network attributes. MyProteinNet is particularly geared toward building human tissue interactomes, by maintaining tissue expression profiles from multiple resources. The ability of MyProteinNet to facilitate the construction of up-to-date, context-specific interactomes and its applicability to 11 different organisms and to tens of human tissues, make it a powerful tool in meaningful analysis of protein networks. MyProteinNet is available at http://netbio.bgu.ac.il/myproteinnet.

Identification of hybrid node and link communities in complex networks

Abstract: Identifying communities in complex networks is an effective means for analyzing complex systems, with applications in diverse areas such as social science, engineering, biology and medicine. Finding communities of nodes and finding communities of links are two popular schemes for network analysis. These schemes, however, have inherent drawbacks and are inadequate to capture complex organizational structures in real networks. We introduce a new scheme and an effective approach for identifying complex mixture structures of node and link communities, called hybrid node-link communities. A central piece of our approach is a probabilistic model that accommodates node, link and hybrid node-link communities. Our extensive experiments on various real-world networks, including a large protein-protein interaction network and a large network of semantically associated words, illustrated that the scheme for hybrid communities is superior in revealing network characteristics. Moreover, the new approach outperformed the existing methods for finding node or link communities separately.

Detecting Protein Complexes from Signed Protein-Protein Interaction Networks

Abstract: Identification of protein complexes is fundamental for understanding the cellular functional organization. With the accumulation of physical protein-protein interaction (PPI) data, computational detection of protein complexes from available PPI networks has drawn a lot of attentions. While most of the existing protein complex detection algorithms focus on analyzing the physical protein-protein interaction network, none of them take into account the “signs” (i.e., activation-inhibition relationships) of physical interactions. As the “signs” of interactions reflect the way proteins communicate, considering the “signs” of interactions can not only increase the accuracy of protein complex identification, but also deepen our understanding of the mechanisms of cell functions. In this study, we proposed a novel Signed Graph regularized Nonnegative Matrix Factorization (SGNMF) model to identify protein complexes from signed PPI networks. In our experiments, we compared the results collected by our model on signed PPI networks with those predicted by the state-of-the-art complex detection techniques on the original unsigned PPI networks. We observed that considering the “signs” of interactions significantly benefits the detection of protein complexes. Furthermore, based on the predicted complexes, we predicted a set of signed complex-complex interactions for each dataset, which provides a novel insight of the higher level organization of the cell. All the experimental results and codes can be downloaded from http://mail.sysu.edu.cn/home/stsddq@mail.sysu.edu.cn/dai/others/SGNMF.zip.

Understanding Dynamic Social Grouping Behaviors of Pedestrians

Abstract: There have been many studies in the literature on social group recognition of crowds of pedestrians. However, most of these studies have approached the problem from a static point of view. A study on the dynamic property of social groups among people over time can provide significant insight into human behaviors and events. Inspired by sociological models of human collective behavior, in this work, we present a framework for characterizing hierarchical social groups based on evolving tracklet interaction network (ETIN) where the tracklets of pedestrians are represented as nodes and the their grouping behaviors are captured by the edges with associated weights. We use non-overlapping snapshots of the interaction network and develop the framework for a unified dynamic group identification and tracklet association. The approach is evaluated quantitatively and qualitatively on videos of pedestrian scenes where manually labeled ground-truth is given. The results of our approach are consistent to human-perceived dynamic social groups of the crowd. The performance analysis of our method shows that the approach is scalable and it provides situational awareness in a real-world scenarios.

Development and application of an interaction network ontology for literature mining of vaccine-associated gene-gene interactions.

Abstract: Literature mining of gene-gene interactions has been enhanced by ontology-based name classifications. However, in biomedical literature mining, interaction keywords have not been carefully studied and used beyond a collection of keywords. In this study, we report the development of a new Interaction Network Ontology (INO) that classifies >800 interaction keywords and incorporates interaction terms from the PSI Molecular Interactions (PSI-MI) and Gene Ontology (GO). Using INO-based literature mining results, a modified Fisher’s exact test was established to analyze significantly over- and under-represented enriched gene-gene interaction types within a specific area. Such a strategy was applied to study the vaccine-mediated gene-gene interactions using all PubMed abstracts. The Vaccine Ontology (VO) and INO were used to support the retrieval of vaccine terms and interaction keywords from the literature. INO is aligned with the Basic Formal Ontology (BFO) and imports terms from 10 other existing ontologies. Current INO includes 540 terms. In terms of interaction-related terms, INO imports and aligns PSI-MI and GO interaction terms and includes over 100 newly generated ontology terms with ‘INO_’ prefix. A new annotation property, ‘has literature mining keywords’, was generated to allow the listing of different keywords mapping to the interaction types in INO. Using all PubMed documents published as of 12/31/2013, approximately 266,000 vaccine-associated documents were identified, and a total of 6,116 gene-pairs were associated with at least one INO term. Out of 78 INO interaction terms associated with at least five gene-pairs of the vaccine-associated sub-network, 14 terms were significantly over-represented (i.e., more frequently used) and 17 under-represented based on our modified Fisher’s exact test. These over-represented and under-represented terms share some common top-level terms but are distinct at the bottom levels of the INO hierarchy. The analysis of these interaction types and their associated gene-gene pairs uncovered many scientific insights. INO provides a novel approach for defining hierarchical interaction types and related keywords for literature mining. The ontology-based literature mining, in combination with an INO-based statistical interaction enrichment test, provides a new platform for efficient mining and analysis of topic-specific gene interaction networks.

Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution.

Abstract: Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib) and promiscuous (Bosutinib, Dasatinib) kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations of key mediating residues. This study has outlined mechanisms by which inhibitor binding could modulate resilience and efficiency of allosteric interactions in the kinase structures, while preserving structural topology required for catalytic activity and regulation.

Differential co-expression network centrality and machine learning feature selection for identifying susceptibility hubs in networks with scale-free structure.

Abstract: Biological insights into group differences, such as disease status, have been achieved through differential co-expression analysis of microarray data. Additional understanding of group differences may be achieved by integrating the connectivity structure of the differential co-expression network and per-gene differential expression between phenotypic groups. Such a global differential co-expression network strategy may increase sensitivity to detect gene-gene interactions (or expression epistasis) that may act as candidates for rewiring susceptibility co-expression networks. We test two methods for inferring Genetic Association Interaction Networks (GAIN) incorporating both differential co-expression effects and differential expression effects: a generalized linear model (GLM) regression method with interaction effects (reGAIN) and a Fisher test method for correlation differences (dcGAIN). We rank the importance of each gene with complete interaction network centrality (CINC), which integrates each gene’s differential co-expression effects in the GAIN model along with each gene’s individual differential expression measure. We compare these methods with statistical learning methods Relief-F, Random Forests and Lasso. We also develop a mixture model and permutation approach for determining significant importance score thresholds for network centralities, Relief-F and Random Forest. We introduce a novel simulation strategy that generates microarray case–control data with embedded differential co-expression networks and underlying correlation structure based on scale-free or Erdos-Renyi (ER) random networks. Using the network simulation strategy, we find that Relief-F and reGAIN provide the best balance between detecting interactions and main effects, plus reGAIN has the ability to adjust for covariates and model quantitative traits. The dcGAIN approach performs best at finding differential co-expression effects by design but worst for main effects, and it does not adjust for covariates and is limited to dichotomous outcomes. When the underlying network is scale free instead of ER, all interaction network methods have greater power to find differential co-expression effects. We apply these methods to a public microarray study of the differential immune response to influenza vaccine, and we identify effects that suggest a role in influenza vaccine immune response for genes from the PI3K family, which includes genes with known immunodeficiency function, and KLRG1, which is a known marker of senescence.

Construction of phosphorylation interaction networks by text mining of full-length articles using the eFIP system.

Abstract: Protein phosphorylation is a reversible post-translational modification where a protein kinase adds a phosphate group to a protein, potentially regulating its function, localization and/or activity. Phosphorylation can affect protein-protein interactions (PPIs), abolishing interaction with previous binding partners or enabling new interactions. Extracting phosphorylation information coupled with PPI information from the scientific literature will facilitate the creation of phosphorylation interaction networks of kinases, substrates and interacting partners, toward knowledge discovery of functional outcomes of protein phosphorylation. Increasingly, PPI databases are interested in capturing the phosphorylation state of interacting partners. We have previously developed the eFIP (Extracting Functional Impact of Phosphorylation) text mining system, which identifies phosphorylated proteins and phosphorylation-dependent PPIs. In this work, we present several enhancements for the eFIP system: (i) text mining for full-length articles from the PubMed Central open-access collection; (ii) the integration of the RLIMS-P 2.0 system for the extraction of phosphorylation events with kinase, substrate and site information; (iii) the extension of the PPI module with new trigger words/phrases describing interactions and (iv) the addition of the iSimp tool for sentence simplification to aid in the matching of syntactic patterns. We enhance the website functionality to: (i) support searches based on protein roles (kinases, substrates, interacting partners) or using keywords; (ii) link protein entities to their corresponding UniProt identifiers if mapped and (iii) support visual exploration of phosphorylation interaction networks using Cytoscape. The evaluation of eFIP on full-length articles achieved 92.4% precision, 76.5% recall and 83.7% F-measure on 100 article sections. To demonstrate eFIP for knowledge extraction and discovery, we constructed phosphorylation-dependent interaction networks involving 14-3-3 proteins identified from cancer-related versus diabetes-related articles. Comparison of the phosphorylation interaction network of kinases, phosphoproteins and interactants obtained from eFIP searches, along with enrichment analysis of the protein set, revealed several shared interactions, highlighting common pathways discussed in the context of both diseases.

Predicting target-ligand interactions using protein ligand-binding site and ligand substructures

Abstract: Cell proliferation, differentiation, Gene expression, metabolism, immunization and signal transduction require the participation of ligands and targets. It is a great challenge to identify rules governing molecular recognition between chemical topological substructures of ligands and the binding sites of the targets. We suppose that the ligand-target interactions are determined by ligand substructures as well as the physical-chemical properties of the binding sites. Therefore, we propose a fragment interaction model (FIM) to describe the interactions between ligands and targets, with the purpose of facilitating the chemical interpretation of ligand-target binding. First we extract target-ligand complexes from sc-PDB database, based on which, we get the target binding sites and the ligands. Then we represent each binding site as a fragment vector based on a target fragment dictionary that is composed of 199 clusters (denoted as fragements in this work) obtained by clustering 4200 trimers according to their physical-chemical properties. And then, we represent each ligand as a substructure vector based on a dictionary containing 747 substructures. Finally, we build the FIM by generating the interaction matrix M (representing the fragment interaction network), and the FIM can later be used for predicting unknown ligand-target interactions as well as providing the binding details of the interactions. The five-fold cross validation results show that the proposed model can get higher AUC score (92%) than three prevalence algorithms CS-PD (80%), BLM-NII (85%) and RF (85%), demonstrating the remarkable predictive ability of FIM. We also show that the ligand binding sites (local information) overweight the sequence similarities (global information) in ligand-target binding, and introducing too much global information would be harmful to the predictive ability. Moreover, The derived fragment interaction network can provide the chemical insights on the interactions. The target and ligand bindings are local events, and the local information dominate the binding ability. Though integrating of the global information can promote the predictive ability, the role is very limited. The fragment interaction network is helpful for understanding the mechanism of the ligand-target interaction.

Analyzing complex networks through correlations in centrality measurements

Abstract: Many real world systems can be expressed as complex networks of interconnected nodes. It is frequently important to be able to quantify the relative importance of the various nodes in the network, a task accomplished by defining some centrality measures, with different centrality definitions stressing different aspects of the network. It is interesting to know to what extent these different centrality definitions are related for different networks. In this work, we study the correlation between pairs of a set of centrality measures for different real world networks and two network models. We show that the centralities are in general correlated, but with stronger correlations for network models than for real networks. We also show that the strength of the correlation of each pair of centralities varies from network to network. Taking this fact into account, we propose the use of a centrality correlation profile, consisting of the values of the correlation coefficients between all pairs of centralities of interest, as a way to characterize networks. Using the yeast protein interaction network as an example we show also that the centrality correlation profile can be used to assess the adequacy of a network model as a representation of a given real network.

Identification of important interacting proteins (IIPs) in Plasmodium falciparum using large-scale interaction network analysis and in-silico knock-out studies

Abstract: Plasmodium falciparum causes the most severe form of malaria and affects 3.2 million people annually. Due to the increasing incidence of resistance to existing drugs, there is a growing need to discover new and more effective drugs against malaria. Despite the global importance of P. falciparum, vast majority of its proteins are uncharacterized experimentally. Application of newer approaches using several “omics” data has become successful for exploring the biological interactions underlying cellular processes. Till date not many system level study has been published using P. falciparum protein protein interaction. Hence, the purpose of this study is to develop a standardized pipeline for structural, functional, and topographical analysis of large scale protein protein interaction network (PPIN) in order to identify proteins important for network topology and integrity. Here, P. falciparum PPIN has been utilized as a model for better understanding of the molecular mechanisms of survival and pathogenesis of malaria parasite. Various graph theoretical approaches were implemented to identify highly interacting hub and central proteins that are crucial for network integrity. Further, potential network perturbing proteins via an in-silico knock-out (KO) analysis to isolate important interacting proteins (IIPs), which in principle, can elicit significant impact on the global and local environments of the P. falciparum interaction network. 177 hubs and 132 central proteins were identified from the malarial (proteins: 1607; interactions: 4750) PPI networks. Using the in-silico knock-out exercise 131 and 99 global and local network perturbing proteins were also identified. Finally, 271 proteins from P. falciparum were shortlisted as important interacting proteins (IIPs), which not only play crucial role in intra-pathogen network integrity, stage specificity but also interact with various human proteins involved in multiple metabolic pathways within the host cell. These IIPs could be used as potential drug targets in malarial research. Graph theoretical analysis of PPIN can be a very useful approach to identify proteins that are important for regulation of the interactions required for an organism’s survival. Important interacting proteins (IIPs) identified using P. falciparum PPIN provides a useful dataset containing probable candidates for future drug target analysis.