the rational design of many types of biological experiments is greatly facilitated by insights into the molecular mechanisms of biological macromolecules gained from their 3d structures . working molecules of living cells are in the focus of several systematic structural genomics efforts ( 1 ) . although tremendous progress has been made in experimental structure determination by x - ray crystallography and nmr in recent years , the number of structurally characterized proteins is still small compared with the number of known protein sequences : while the uniprot protein knowledge base ( 2 ) reported more than 2 million sequence entries in september 2005 , at the same time only 35  000 database entries for experimentally determined protein structures were deposited in the protein data bank ( pdb ) ( 3 ) . a wide spectrum of computational methods to predict the 3d structures of proteins has been developed to overcome this limitation , ranging from ab initio methods aiming to predict protein structures without prior knowledge , to comparative modelling approaches making use of information from experimentally determined protein structures . as the 3d structures of proteins are better conserved than their sequences ( 4 ) , the experimentally known structure of one protein can be used as template to generate a model for other proteins of the same family sharing sufficient sequence homology ( target ) . the accuracy and reliability of different structure prediction approaches have been assessed in several rounds of casp ( critical assessment of techniques for protein structure prediction ) experiments ( 5 ) . comparative ( or homology ) modelling has been shown to be the most accurate method ( 6 ) , able to reliably build 3d protein models with sufficient accuracy for applications such as structure - based drug design , or rationalizing the effects of sequence variations ( 79 ) . all homology modelling approaches consist of the following four steps : identification of suitable template structure(s ) , alignment of template structure(s ) and target sequence , building of one or more 3d model(s ) , and model quality evaluation . these steps can be repeated iteratively until a satisfying modelling result is achieved and the best model is selected ( 7,10 ) . the number of structurally uncharacterized protein sequences is huge and growing constantly , and at the same time new template structures are being determined by individual research groups or structural genomics efforts ( 1 ) . fully automated , stable and reliable modelling pipelines ( 1113 ) had to be created to handle this steady flow of new data . swiss - model has been established as an expert system for automated homology modelling , integrating the necessary databases , tools and computing resources in an easy to use web - based modelling workbench ( 11,14 ) . the accuracy and reliability of the swiss - model server are continuously monitored by the eva - cm evaluation project ( 15 ) . interactive modelling servers require significant time to complete a certain modelling request , whereas model databases provide instant and queryable access to pre - computed models . databases of models generated by automated procedures on large scale , such as swiss - model repository ( 16 ) or modbase ( 17 ) , give easy access to regularly updated homology models and thereby help to enrich other database projects with structural information . structural genomics projects and model databases complement one another in the coverage of the protein structure space ( 18 ) . in this paper the swiss - model repository is a database of annotated 3d protein models created by the fully automated swiss - model server pipeline ( 14 ) . the model database can be accessed via a web interface , and the models are freely available at . for a given uniprot entry , a model navigator indicates those regions in the protein , where 3d models are available and allows for fast selection of the individual models . the navigator has been extended to incorporate biological annotations via interpro classification ( 19 ) , and , in combination with the target sequence info view , provides the user with detailed information about the target sequence . the model section ( figure 1a ) presents a summary for each individual model , including information about the template structure , and the target - template alignment used for model building . detailed modelling and template selection logs contain essential information about the modelling process , e.g. handling of insertions and deletions . as quality evaluation is indispensable for a predictive method like homology modelling , graphical representations of model assessment by anolea mean force potentials ( 20 ) and gromos force field energy ( 21 ) are given for each model ( figure 1d ) . the number of models in the repository has more than doubled over the last two years . as of september 2005 , the swiss - model repository contained 675  000 protein models for 604  000 distinct uniprot ( release 5.8 ) entries . for 75  150 ( 39% ) swissprot entries ( release 47.8 ) and 528  932 ( 27% ) trembl ( release 30.8 ) entries a significant part of the sequence could be modelled . this corresponds to a per - residue coverage of 28% for swissprot and 17% for trembl . model sizes range from 44 residues for the shortest model to 1512 residues for the longest model ( ferredoxin - dependent glutamate synthase from anabena sp . ) , with an average model size of 200 amino acids . of all models 25% correspond to bacterial proteins , 1% to archaea , 28% to viruses and 46% to eukaryotic proteins , including 4.3% human sequences . the aim of the swiss - model repository is to provide accurate models suitable for the design of biological experiments . therefore , care was taken to include only models with a high level of confidence , i.e. reliable target - template alignments with a sequence identity higher than 40% , and acceptable evaluation results by anolea ( 20 ) and gromos ( 21 ) . a subset of high quality models of the repository is complementing the structural information available in these two databases . each entry in the repository contains a sequence - based crc64 checksum , which uniquely identifies its corresponding amino acid sequence and guarantees data consistency when exchanging records between different databases . moreover , this mechanism can also ensure that hyperlinks between websites using uniprot accession codes are referencing identical protein sequences . therefore hyperlinks to the swiss - model repository consist of the url , a uniprot accession code , and optionally the start residue of a model , and the crc64 checksum of the amino acid sequence . the interpretation of biological annotations of a protein sequence in the context of its 3d structure is of great help for a detailed understanding of its molecular function . each target sequence in the repository has a short protein description with links to relevant sequence based resources . a graphical representation of the interpro functional and domain level annotations of the target sequence indicates regions of functional and structural importance in the target sequence ( figure 1b ) . their location relative to the available models can be visualized directly from the website using the interactive java based astexviewer applet ( 22 ) enabling the user to analyse biologically significant substructures . alternatively , model coordinates can be downloaded for visualization ( figure 1c ) , and further analysis using specialized software , such as deepview ( 11 ) , dino ( ) or rasmol ( 23 ) . computing an entire release of the repository takes several weeks on our in - house linux cluster and is done when major changes have been implemented , e.g. algorithmic improvements in the pipeline . fast integration of new sequence data and new experimentally determined protein structures released by the pdb ( 3 ) is a big benefit for the user , but poses a challenge to the update capability of the model database . we therefore established an incremental update procedure which takes into account new template structures , new protein sequence entries and modified sequences in uniprot . when new experimentally determined structures become available , models are generated for those proteins , which could not be modelled previously , and existing models are updated for those proteins , for which better templates are identified among the newly released structures . current data status of the swiss - model repository is shown on the entry page . the automated modelling pipeline performs a sequence based search of the swiss - model template library to select the best template to model a specific region of the target sequence , favouring template structures with high resolution ( 14 ) . however , the template selection log lists all template structures identified during the template search with links to the swiss - model template library . for each putative template , information about experimental details , likely quaternary structure ( 24 ) , bound ligands , and links to external structure databases , such as scop ( 25 ) , cath ( 26 ) and msd ( 27 ) , are provided accompanied by a small ribbon representation . this enables the user to select alternative templates , e.g. templates with or without ligand , open or closed conformations , multimeric structures , which might be more appropriate for the specific modelling task , and to continue the modelling project using the interactive swiss - model server architecture . the number of models in the repository has more than doubled over the last two years . as of september 2005 , the swiss - model repository contained 675  000 protein models for 604  000 distinct uniprot ( release 5.8 ) entries . for 75  150 ( 39% ) swissprot entries ( release 47.8 ) and 528  932 ( 27% ) trembl ( release 30.8 ) entries a significant part of the sequence could be modelled . this corresponds to a per - residue coverage of 28% for swissprot and 17% for trembl . model sizes range from 44 residues for the shortest model to 1512 residues for the longest model ( ferredoxin - dependent glutamate synthase from anabena sp . ) , with an average model size of 200 amino acids . of all models 25% correspond to bacterial proteins , 1% to archaea , 28% to viruses and 46% to eukaryotic proteins , including 4.3% human sequences . the aim of the swiss - model repository is to provide accurate models suitable for the design of biological experiments . therefore , care was taken to include only models with a high level of confidence , i.e. reliable target - template alignments with a sequence identity higher than 40% , and acceptable evaluation results by anolea ( 20 ) and gromos ( 21 ) . a subset of high quality models of the repository is complementing the structural information available in these two databases . each entry in the repository contains a sequence - based crc64 checksum , which uniquely identifies its corresponding amino acid sequence and guarantees data consistency when exchanging records between different databases . moreover , this mechanism can also ensure that hyperlinks between websites using uniprot accession codes are referencing identical protein sequences . therefore hyperlinks to the swiss - model repository consist of the url , a uniprot accession code , and optionally the start residue of a model , and the crc64 checksum of the amino acid sequence . the interpretation of biological annotations of a protein sequence in the context of its 3d structure is of great help for a detailed understanding of its molecular function . each target sequence in the repository has a short protein description with links to relevant sequence based resources . a graphical representation of the interpro functional and domain level annotations of the target sequence indicates regions of functional and structural importance in the target sequence ( figure 1b ) . their location relative to the available models can be visualized directly from the website using the interactive java based astexviewer applet ( 22 ) enabling the user to analyse biologically significant substructures . alternatively , model coordinates can be downloaded for visualization ( figure 1c ) , and further analysis using specialized software , such as deepview ( 11 ) , dino ( ) or rasmol ( 23 ) . computing an entire release of the repository takes several weeks on our in - house linux cluster and is done when major changes have been implemented , e.g. algorithmic improvements in the pipeline . fast integration of new sequence data and new experimentally determined protein structures released by the pdb ( 3 ) is a big benefit for the user , but poses a challenge to the update capability of the model database . we therefore established an incremental update procedure which takes into account new template structures , new protein sequence entries and modified sequences in uniprot . when new experimentally determined structures become available , models are generated for those proteins , which could not be modelled previously , and existing models are updated for those proteins , for which better templates are identified among the newly released structures . current data status of the swiss - model repository is shown on the entry page . the automated modelling pipeline performs a sequence based search of the swiss - model template library to select the best template to model a specific region of the target sequence , favouring template structures with high resolution ( 14 ) . however , the template selection log lists all template structures identified during the template search with links to the swiss - model template library . for each putative template , information about experimental details , likely quaternary structure ( 24 ) , bound ligands , and links to external structure databases , such as scop ( 25 ) , cath ( 26 ) and msd ( 27 ) , are provided accompanied by a small ribbon representation . this enables the user to select alternative templates , e.g. templates with or without ligand , open or closed conformations , multimeric structures , which might be more appropriate for the specific modelling task , and to continue the modelling project using the interactive swiss - model server architecture . swiss - model repository entry for cyclodextrin glucanotransferase from bacillus stearothermophilus ( uniprot : q9zaq0 ) . ( a ) the  model info section provides a description of the template structure , the target - template alignment and a log of the modelling process . ( b ) annotation of functional sites and individual domains of the target protein using interpro assignments . ( c ) structure of the model as ribbon representation using deepview / povray coloured according to interpro assignments .
the swiss - model repository is a database of annotated 3d protein structure models generated by the swiss - model homology - modelling pipeline . as of september 2005 
 , the repository contained 675  000 models for 604  000 different protein sequences of the uniprot database . 
 regular updates ensure that the content of the repository reflects the current state of sequence and structure databases , integrating new or modified target sequences , and making use of new template structures . 
 each repository entry consists of one or more 3d models accompanied by detailed information about the target protein and the model building process : functional annotation , a detailed template selection log , target - template alignment , summary of the model building and model quality assessment . 
 the swiss - model repository is freely accessible at .