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Over the last decade, new biological data and discovery has extended our ability to interrogate and view biological process at many levels of granularity. In particular, techniques and tools have been developed to look at biological function from a systems perspective rather than a molecular perspective. This approach, utilized by systems biologists, stresses the importance of biological context, whether evolutionary, developmental, genetic, metabolic, environmental, or signaling-related, in the understanding of how organisms function and react to external stimuli. Biological context is now accepted as critical for understanding function in proteins (Boeckmann, 2005), gene regulation (Cohen, 2006), and metabolic pathways (Mlecnik, 2005).

Systems biologists often address research questions from a top-down perspective aimed at explicitly modeling the complexity inherent in biological organisms. At the other end of the spectrum, molecular and structural biologists contribute to systems biology via a bottom-up approach focused on identifying the "parts list" of an organism, then determining how the individual parts interact. These two approaches increasingly overlap. Systems approaches now have the resolution to pose hypotheses about the interactions of individual proteins or the roles of specific metabolites in a pathway. Similarly, molecular and structural biologists are increasingly investigating the impact of regulatory pathways on transcription and how larger complexes of proteins work together to perform some biological function. As systems biology increases in resolution and molecular and structural biology increase in scope, we believe that there is a critical need to integrate tools commonly used within each discipline. From the perspective of the molecular or structural biologist, integration should facilitate understanding the biological context of the molecule or system under study. From the perspective of the systems biologist, integration should provide access to the molecular and structural details of the interactions observed at the macro level.

Cytoscape (Shannon, 2003), a widely used open-source network visualization tool, provides a broad context for exploring sequence→structure→function relationships. Cytoscape provides an excellent plugin mechanism that will allow us to extend its functionality to meet our needs. Examples of Cytoscape plugins include BiNGO (Maere, 2005), which maps Gene Ontology information to Cytoscape nodes; cPath, which allows users to query retrieve and visualize data from the cancer pathway (cPath) database; and the PhenoType Genetics plugin, which constructs genetic-interaction networks from large sets of phenotype measurements.

Cytoscape is an excellent tool, but it has not been widely used for sequence→structure→function studies in general, nor are there any specific connections to three-dimensional structures beyond the ability to annotate nodes. Enhancing this widely used tool will benefit users of our resource directly, and will also benefit members of the much broader research community who are working with sequence, structure, and function at a scale that requires the visualization of both context and detail. This network view provides the starting point to explore details of interactions such as the sequence-structure comparisons and visualization provided by Chimera.

Cytoscape Plugins developed or supported by the UCSF RBVI

Please note: researchers using these tools are kindly requested to acknowledge the UCSF Resource for Biocomputing, Visualization, and Informatics (http://www.rbvi.ucsf.edu), funded by NIH grant P41 RR01081.

structureViz

A plugin that provides a direct link between Cytoscape and UCSF Chimera

clusterMaker

clusterMaker is a Cytoscape plugin that unifies a number of different clustering techniques and visualization styles into a single interface.

chemViz

chemViz is a Cytoscape plugin that extends the capabilities of Cytoscape into the domain of cheminformatics.

Shortest Path

A version of the shortest-path plugin developed by Marcio Rosa da Silva that utilizes a user-specified edge attribute as a weighting value to compute the length.

MetaNodes

The library and plugin originally developed by Iliana Avila-Campillo from the Institute for Systems Biology for collapsing and expanding groups of nodes.

Edge-weighted layout

A layout plugin based on the Fruchterman-Reingold and Kamada-Kawai algorithms, but modified to utilize a user-specified edge attribute as a weighting value to compute the attractive forces of an edge. This work has now been integrated into the Cytoscape core plugin AutomaticLayout.jar.

Publications from RBVI projects

• Morris JH, Huang CC, Babbitt PC, Ferrin TE. structureViz: linking Cytoscape and UCSF Chimera. Bioinformatics 2007 Sep 1;23(17):2345-7.
• Atkinson HJ, Morris JH, Ferrin TE, Babbitt PC. Using sequence similarity networks for visualization of relationships across diverse protein superfamilies. PLoS One 2009; 4(2): e4345. [Supplementary Data]
• Apeltsin L, Morris JH, Huang CC, Brown SD, Babbitt PC, Ferrin TE. A Filtration Protocol for Elucidating Relationships between Families in a Protein Similarity Network. [submitted for publication] [source code]

References

• Boeckmann B, Blatter MC, Famiglietti L, Hinz U, Lane L, Roechert B, Bairoch A: Protein variety and functional diversity: Swiss-Prot annotation in its biological context. C R Biol 2005, 328(10-11):882-899.
• Cohen CD, Klingenhoff A, Boucherot A, Nitsche A, Henger A, Brunner B, Schmid H, Merkle M, Saleem MA, Koller KP et al: Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins. Proc Natl Acad Sci U S A 2006, 103(15):5682-5687.
• Mlecnik B, Scheideler M, Hackl H, Hartler J, Sanchez-Cabo F, Trajanoski Z: PathwayExplorer: web service for visualizing high-throughput expression data on biological pathways. Nucleic Acids Res 2005, 33(Web Server issue):W633-637.
• Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003, 13(11):2498-2504.
• Maere S, Heymans K, Kuiper M: BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 2005, 21(16):3448-3449.

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