Bioinformatics Advance Access originally published online on September 7, 2004
Bioinformatics 2005 21(3):410-412; doi:10.1093/bioinformatics/bti011
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Bioinformatics vol. 21 issue 3 © Oxford University Press 2005; all rights reserved.
iPfam: visualization of protein–protein interactions in PDB at domain and amino acid resolutions
The Wellcome Trust Sanger Institute The Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
*To whom correspondence should be addressed.
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Summary: There are many resources that contain information about binary interactions between proteins. However, protein interactions are defined by only a subset of residues in any protein. We have implemented a web resource that allows the investigation of protein interactions in the Protein Data Bank structures at the level of Pfam domains and amino acid residues. This detailed knowledge relies on the fact that there are a large number of multidomain proteins and protein complexes being deposited in the structure databases. The resource called iPfam is hosted within the Pfam UK website. Most resources focus on the interactions between proteins; iPfam includes these as well as interactions between domains in a single protein.
Availability: iPfam is available on the Web for browsing at http://www.sanger.ac.uk/Software/Pfam/iPfam/; the source-data for iPfam is freely available in relational tables via the ftp site ftp://ftp.sanger.ac.uk/pub/databases/Pfam/database_files/
Contact: rdf{at}sanger.ac.uk
Although we often consider proteins in isolation, it now seems likely that the majority of proteins in the cell are parts of large molecular complexes (Gavin et al., 2002; Uetz et al., 2000). Information on these complexes and the protein–protein interactions that they are composed of are being collected in databases, such as DIP (Salwinski et al., 2004), MINT (Zanzoni et al., 2002), BIND (Bader et al., 2003) and IntAct (Hermjakob et al., 2004). The large majority of data in these databases presents binary information, which states that protein A interacts with protein B. Although this is useful, we would often like to know which specific region of the proteins are interacting, e.g. which domains are interacting. This may be between two different proteins (interchain interaction) or for many cases the interactions is between two domains within a single protein (intrachain interaction). Inference on these domain interactions from binary interactions has been attempted (Deng et al., 2002) but is not yet sensitive or reliable. To understand how protein domains interact at the molecular level, we need to know which residues, and their constituent atoms, in each protein are interacting. These kind of data are available in the Protein Data Bank (PDB) database of protein structures (Bourne et al., 2004) where multiple domains are present in a single structure. However, these residue level interaction data are not readily accessible to a biologist to use, and even a structural biologist would require some time to define them.
To identify interactions at the level of amino acid residues one has to define where the domains lie in the structure. Domains need to be defined on the structure as we need to distinguish between interactions that occur between amino acids within the domains and interactions between amino acids from another domain. To define domains in iPfam, we use the domain definitions from Pfam (Bateman et al., 2004) projected onto the PDB structures using the UniProt (Apweiler et al., 2004) to PDB mapping provided by the MSD (Golovin et al., 2004). To identify the interactions between residues, we calculate all bonds (van der Waals, side chain and main chain H-bonds, salt bridge and disulphide) between all pairs of residues in different domains. These bonds can be between domains within the same chain or between domains in different chains in the structure.
iPfam contains interactions among 2733 different pairs of domains (as of Pfam release 12.0). These domain–domain interactions can readily be browsed via the UK Pfam website (http://www.sanger.ac.uk/Software/Pfam/iPfam/browse/number.shtml). For each domain page in Pfam with a known domain–domain interaction in the PDB, we provide a link to the iPfam resource. For each protein structure we provide a domain interaction network, as shown in Figure 1, which readily conveys information about which domains in a structure are interacting directly. This graph representation is generated using the GraphViz package (http://www.research.att.com/sw/tools/graphviz/). On this page, we also provide the facility to view the interaction in more detail. We allow visualization of the PDB structure with the interacting residues marked up using Rasmol (Sayle and Milner-White, 1995), and we plan to add viewing with Jmol in the near future (http://jmol.sourceforge.net/). A link from this page also allows users to browse the interaction data at the level of amino acid residue. Figure 2 shows how this information is displayed. By zooming in on the interaction picture one can get exact residue interactions. Although we store the bond types in our relational database, we do not display this information currently. Users interested in this fine grained annotation can download the relational tables for local use.
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iPfam also allows one to look at the conservation of domain–domain interactions between different PDB entries of the same protein. This allows users to discern which residues are conserved in the domain–domain interface.
To our knowledge, this is the first comprehensive site that allows non-experts to access detailed domain interactions available in the protein structures. We hope that this growing dataset will improve our understanding of protein–protein interactions.
Received on May 20, 2004; revised on August 9, 2004; accepted on August 29, 2004
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