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## Basic Information

Doncheva NT, Assenov Y, Domingues FS, Albrecht M. Topological analysis and interactive visualization of biological networks and protein structures. Nat Protoc. 2012;7(4):670‐685. Published 2012 Mar 15. doi:10.1038/nprot.2012.004

• Computational analysis and interactive visualization of:
• biological networks
• protein structures
• Workflows based on the NetworkAnalyzer and RINalyzer plug-ins for Cytoscape
• NetworkAnalyzer: comprehensive network topology analysis
• RINalyzer: provides methods for exploring residue interaction networks derived from protein structures

## NetworkAnalyzer

### Topological parameters

• node degree
• clustering
• topological coefficient
• characteristic path length
• betweeness centrality

## RINalyzer

It complements NetworkAnalyzer on the particular task of analyzing and visualizing reisidue interaction networks (RINs) interactively.

A RIN consists of nodes that prepresent protein residues and edges that correspond to noncovalent interacions between residues.

### Versatile user optins

Computation of weighted network centrality measures to highlight biological important residues and the network comparison of superimposed protein structures to study differing residue interactions.

Examples include the identification of key residues for protein folding and allostery, the investigation of residue interactions in protein binding interfaces and active sites, and the detailed characterization of the molecular effects of residue mutation

## Workflows

• The firset workflow uses NetworkAnalyzer and shows how to conduct a typical topology analysis of biological networks such protein interaction networks or RINs.
• The second workflow covers various aspects related to the use of RINalyzer for the visual exploration of RINs, the study of protein binding interfaces and the network centrality analysis.
• The third workflow details how to combine NetworkAnalyzer and RINalyzer for the comparison of multiple RINs.

## Experimental Design

### Topological analysis of biological networks

This workflow descries how to use the NetworkAnalyzer plug-in to perform a topological analysis of an unweighted network loaded in to Cytoscape, as well as how to process and visualize the result.

### Interactive visual analysis of residue networks

This workflow explains the use of tht Cytoscape plug-in RINalyzer and its features for analyzing and visualizing RINs.

The workflow starts with the retrieval of reisdue interaction data for a protein of interset from the web interface to our RINdata database. It contains RINs generated by means of the RINerator software for over 5,000 protein structures from the PDB. In contrast to previous approaches that define residue interactions on the basis of spatial atomic distance between residues, RINerator distinguishes different residue interaction types and quantifies the strength of individual interactions, which results in an undirected weighted network with multiple interactions edges. To this end, RINerator first adds hydrogens to the 3D protein structure by using the Reduce tool and then samples contacts on the van der Waals surface of each atom by using Probe.

In a RIN, the nodes represent the protein residues and the edges between them represent the noncovalent interactions identified by Probe. The edges are labeled with an interaction type and subtype. Possible types are interatomic contact (cnt), hydrogen bond (hbond), overlapping van der Waals radii (ovl) and generic residue interac-tion (combi), whereas the subtypes indicate interactions between main chains (mc) and side chains (sc) of the amino acid residues. Each edge is weighted with the respective score for the interacting residues as computed by Probe and the weight is proportional to the strength of the interaction. The resulting RIN and additional information (such as edge weights) are stored in the Cytoscape default formats, the simple interaction format (SIF) for the net-work, and the edge attribute (EA) files for the edge weights34. Thus, each RIN is accompanied by the original PDB file with hydrogens added, and two edge attribute files.

Once both the RIN and the corresponding protein structure are imported (after Step 2B(iv)), RINalyzer establishes a bidirec-tional connection between Cytoscape and the 3D structure viewer UCSF Chimera.

### Comparison of residue networks

This workflow introduces one possible application scenario that combines NetworkAnalyzer and RINalyzer.