Analyzing and visualizing residue networks of protein structures

The study of individual amino acid residues and their molecular interactions in protein structures is crucial for understanding structure-function relationships. Recent work has indicated that residue networks derived from 3D protein structures provide additional insights into the structural and functional roles of interacting residues. Here, we present the new software tools RINerator and RINalyzer for the automatized generation, 2D visualization, and interactive analysis of residue interaction networks, and highlight their use in different application scenarios.     

Computing topological parameters of biological networks

Rapidly increasing amounts of molecular interaction data are being produced by various experimental techniques and computational prediction methods. In order to gain insight into the organization and structure of the resultant large complex networks formed by the interacting molecules, we have developed the versatile Cytoscape plugin NetworkAnalyzer. It computes and displays a comprehensive set of topological parameters, which includes the number of nodes, edges, and connected components, the network diameter, radius, density, centralization, heterogeneity, and clustering coefficient, the characteristic path length, and the distributions of node degrees, neighborhood connectivities, average clustering coefficients, and shortest path lengths. NetworkAnalyzer can be applied to both directed and undirected networks and also contains extra functionality to construct the intersection or union of two networks. It is an interactive and highly customizable application that requires no expert knowledge in graph theory from the user. AVAILABILITY: NetworkAnalyzer can be downloaded via the Cytoscape web site: http://www.cytoscape.org     

Integration of biological networks and gene expression data using Cytoscape

Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.     

Network Analysis Tools: from biological networks to clusters and pathways

Network Analysis Tools (NeAT) is a suite of computer tools that integrate various algorithms for the analysis of biological networks: comparison between graphs, between clusters, or between graphs and clusters; network randomization; analysis of degree distribution; network-based clustering and path finding. The tools are interconnected to enable a stepwise analysis of the network through a complete analytical workflow. In this protocol, we present a typical case of utilization, where the tasks above are combined to decipher a protein-protein interaction network retrieved from the STRING database. The results returned by NeAT are typically subnetworks, networks enriched with additional information (i.e., clusters or paths) or tables displaying statistics. Typical networks comprising several thousands of nodes and arcs can be analyzed within a few minutes. The complete protocol can be read and executed in approximately 1 h.     

structureViz: linking Cytoscape and UCSF Chimera

structureViz is a Cytoscape plug-in that links the visualization of biological networks provided by Cytoscape with the visualization and analysis of macromolecular structures and sequences provided by UCSF Chimera. When combined with Cytoscape and Chimera, structureViz provides the first tool that links these two critical aspects of computational analysis in a straightforward manner. structureViz includes commands to open structures in Chimera and align them using Chimera's sequence-structure analysis tools. When a structure is opened, structureViz provides an alternative interface to Chimera: the Cytoscape Molecular Structure Navigator. This interface uses a tree-based paradigm to allow users to select and affect the display of models, chains and residues, mostly through the use of context menus.     

Cytoscape ESP: simple search of complex biological networks

SUMMARY: Cytoscape enhanced search plugin (ESP) enables searching complex biological networks on multiple attribute fields using logical operators and wildcards. Queries use an intuitive syntax and simple search line interface. ESP is implemented as a Cytoscape plugin and complements existing search functions in the Cytoscape network visualization and analysis software, allowing users to easily identify nodes, edges and subgraphs of interest, even for very large networks. Availabiity: http://chianti.ucsd.edu/cyto_web/plugins/ CONTACT: ashkenaz@agri.huji.ac.il.     

FunMod: A Cytoscape Plugin for Identifying Functional Modules in Undirected Protein–Protein Networks

The characterization of the interacting behaviors of complex biological systems is a primary objective in protein–protein network analysis and computational biology. In this paper we present FunMod, an innovative Cytoscape version 2.8 plugin that is able to mine undirected protein–protein networks and to infer sub-networks of interacting proteins intimately correlated with relevant biological pathways. This plugin may enable the discovery of new pathways involved in diseases. In order to describe the role of each protein within the relevant biological pathways, FunMod computes and scores three topological features of the identified sub-networks. By integrating the results from biological pathway clustering and topological network analysis, FunMod proved to be useful for the data interpretation and the generation of new hypotheses in two case studies.     

Cluster Viz:集成于Cytoscape的聚类可视化插件

生物网络中的聚类分析是功能模块识别及蛋白质功能预测的重要方法,聚类结果的可视化对于快速有效地分析生物网络结构也具有重要作用。通过分析生物网络显示和分析平台Cytoscape的架构,设计了一个使用方便的聚类分析和显示插件ClusterViz。这是一个可扩展的聚类算法的集成平台,可以不断增加其中的聚类算法,并对不同算法的结果进行比较分析,目前已实现了三种典型的算法实例。该插件能够成为蛋白质相互作用网络机理研究的一个有效工具。     

GLay: community structure analysis of biological networks

SUMMARY: GLay provides Cytoscape users an assorted collection of versatile community structure algorithms and graph layout functions for network clustering and structured visualization. High performance is achieved by dynamically linking highly optimized C functions to the Cytoscape JAVA program, which makes GLay especially suitable for decomposition, display and exploratory analysis of large biological networks. AVAILABILITY: http://brainarray.mbni.med.umich.edu/glay/.     

Assembling global maps of cellular function through integrative analysis of physical and genetic networks

To take full advantage of high-throughput genetic and physical interaction mapping projects, the raw interactions must first be assembled into models of cell structure and function. PanGIA (for physical and genetic interaction alignment) is a plug-in for the bioinformatics platform Cytoscape, designed to integrate physical and genetic interactions into hierarchical module maps. PanGIA identifies 'modules' as sets of proteins whose physical and genetic interaction data matches that of known protein complexes. Higher-order functional cooperativity and redundancy is identified by enrichment for genetic interactions across modules. This protocol begins with importing interaction networks into Cytoscape, followed by filtering and basic network visualization. Next, PanGIA is used to infer a set of modules and their functional inter-relationships. This module map is visualized in a number of intuitive ways, and modules are tested for functional enrichment and overlap with known complexes. The full protocol can be completed between 10 and 30 min, depending on the size of the data set being analyzed.     

BiNoM: a Cytoscape plugin for manipulating and analyzing biological networks

BiNoM (Biological Network Manager) is a new bioinformatics software that significantly facilitates the usage and the analysis of biological networks in standard systems biology formats (SBML, SBGN, BioPAX). BiNoM implements a full-featured BioPAX editor and a method of 'interfaces' for accessing BioPAX content. BiNoM is able to work with huge BioPAX files such as whole pathway databases. In addition, BiNoM allows the analysis of networks created with CellDesigner software and their conversion into BioPAX format. BiNoM comes as a library and as a Cytoscape plugin which adds a rich set of operations to Cytoscape such as path and cycle analysis, clustering sub-networks, decomposition of network into modules, clipboard operations and others. AVAILABILITY: Last version of BiNoM distributed under the LGPL licence together with documentation, source code and API are available at http://bioinfo.curie.fr/projects/binom     

RING: networking interacting residues, evolutionary information and energetics in protein structures

MOTIVATION: Residue interaction networks (RINs) have been used in the literature to describe the protein 3D structure as a graph where nodes represent residues and edges physico-chemical interactions, e.g. hydrogen bonds or van-der-Waals contacts. Topological network parameters can be calculated over RINs and have been correlated with various aspects of protein structure and function. Here we present a novel web server, RING, to construct physico-chemically valid RINs interactively from PDB files for subsequent visualization in the Cytoscape platform. The additional structure-based parameters secondary structure, solvent accessibility and experimental uncertainty can be combined with information regarding residue conservation, mutual information and residue-based energy scoring functions. Different visualization styles are provided to facilitate visualization and standard plugins can be used to calculate topological parameters in Cytoscape. A sample use case analyzing the active site of glutathione peroxidase is presented. AVAILABILITY: The RING server, supplementary methods, examples and tutorials are available for non-commercial use at URL: http://protein.bio.unipd.it/ring/.     

基于Cytoscape的蛋白质网络可视化聚类分析插件

蛋白质网络聚类是识别功能模块的重要手段,不仅有利于理解生物系统的组织结构,对预测蛋白质功能也具有重要的意义.聚类结果的可视化分析是实现蛋白质网络聚类的有效途径.本论文基于开源的Cytoscape平台,设计并实现了一个蛋白质网络聚类分析及可视化插件CytoCluster.该插件集成了MCODE,FAG-EC,HC-PIN,OH-PIN,IPCA,EAGLE等六种典型的聚类算法;实现了聚类结果的可视化,将分析所得的clusters以缩略图列表的形式直观地显示出来,对于单个cluster,可显示在原网络中的位置,并能生成相应的子图单独显示;可对聚类结果进行导出,记录了算法名称、参数、聚类结果等信息.该插件具有良好的扩展性,提供了统一的算法接口,可不断添加新的聚类算法.     

Cytoprophet: a Cytoscape plug-in for protein and domain interaction networks inference

Cytoprophet is a software tool that allows prediction and visualization of protein and domain interaction networks. It is implemented as a plug-in of Cytoscape, an open source software framework for analysis and visualization of molecular networks. Cytoprophet implements three algorithms that predict new potential physical interactions using the domain composition of proteins and experimental assays. The algorithms for protein and domain interaction inference include maximum likelihood estimation (MLE) using expectation maximization (EM); the set cover approach maximum specificity set cover (MSSC) and the sum-product algorithm (SPA). After accepting an input set of proteins with Uniprot ID/Accession numbers and a selected prediction algorithm, Cytoprophet draws a network of potential interactions with probability scores and GO distances as edge attributes. A network of domain interactions between the domains of the initial protein list can also be generated. Cytoprophet was designed to take advantage of the visual capabilities of Cytoscape and be simple to use. An example of inference in a signaling network of myxobacterium Myxococcus xanthus is presented and available at Cytoprophet's website. AVAILABILITY: http://cytoprophet.cse.nd.edu.     

Structure-Based Network Analysis of Activation Mechanisms in the ErbB Family of Receptor Tyrosine Kinases: The Regulatory Spine Residues Are Global Mediators of Structural Stability and Allosteric Interactions

The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced “superacceptor” activity in oncogenic EGFR dimers. We have found that kinase activation may be determined by allosteric interactions between modules of structurally stable residues that synchronize the dynamics in the nucleotide binding site and the αC-helix with the collective motions of the integrating αF-helix and the substrate binding site. The results of this study have pointed to a central role of the conserved His-Arg-Asp (HRD) motif in the catalytic loop and the Asp-Phe-Gly (DFG) motif as key mediators of structural stability and allosteric communications in the ErbB kinases. We have determined that residues that are indispensable for kinase regulation and catalysis often corresponded to the high centrality nodes within the protein structure network and could be distinguished by their unique network signatures. The optimal communication pathways are also controlled by these nodes and may ensure efficient allosteric signaling in the functional kinase state. Structure-based network analysis has quantified subtle effects of ATP binding on conformational dynamics and stability of the EGFR structures. Consistent with the NMR studies, we have found that nucleotide-induced modulation of the residue interaction networks is not limited to the ATP site, and may enhance allosteric cooperativity with the substrate binding region by increasing communication capabilities of mediating residues.     

Understanding on the residue contact network using the log‐normal cluster model and the multilevel wheel diagram

Residue clusters play essential role in stabilizing protein structures in the form of complex networks. We show that the cluster sizes in a native protein follow the log‐normal distribution for a dataset consisting of 424 proteins. To our knowledge, this is the first time of such fitting for the native structures. Based on log‐normal model, the asymptotically increasing mean cluster sizes produce a critical protein chain length of about 200 amino acids, beyond which length most globular proteins have nearly the same mean cluster sizes. This suggests that the larger proteins use a different packing mechanism than the smaller proteins. We confirmed the scale‐free property of the residue contact network for most of the protein structures in the dataset, although the violations were observed for the tightly packed proteins. Residue cluster network wheel (RCNW) is proposed to visualize the relationship between the multiple properties of the residue network such as the cluster size, the residue types and contacts, and the flexibility of the residue. We noticed that the residues with large cluster size have smaller Cα displacement measured using the normal mode analysis. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 904–916, 2010.