The SWISS-MODEL Repository and associated resources

Abstract

INTRODUCTION

Three-dimensional protein structures are crucial for understanding protein function at a molecular level. In recent years, tremendous progress in experimental techniques for large-scale protein structure determination by X-ray crystallography and NMR has been achieved. Structural genomic efforts have contributed significantly to the elucidation of novel protein structures (1), and to the development of technologies, which have increased the speed and success rate at which structures can be determined and lowered the cost of the experiments (2,3). However, the number of known protein sequences grows at an ever higher rate as large-scale sequencing projects, such as the Global Ocean Sampling expedition, are producing sequence data at an unprecedented rate (4). Consequently, the last release of the UniProt (5) protein knowledgebase (version 14.0) contained more than 6.5 million sequences, which is about 100 times the number protein structures currently deposited in the Protein Data Bank (6) (∼53 000, September 2008). For the foreseeable future, stable and reliable computational approaches for protein structure modelling will therefore be required to derive structural information for the majority of proteins, and a broad variety of in silico methods for protein structure prediction has been developed in recent years.

Homology (or comparative) modelling techniques have been shown to provide the most accurate models in cases, where experimental structures related to the protein of interest were available. Although the number of protein sequence families increases at a rate that is linear or almost linear with the addition of new sequences (4), the number of distinct protein folds in nature is limited (1,7) and the growth in the complexity of protein families appears as a result of the combination of domains (M. Levitt, manuscript in preparation). Achieving complete structural coverage of whole proteomes (on the level of individual soluble domain structures) by combining experimental and comparative modelling techniques therefore appears to be a realistic goal, and is already been pursued, e.g. by the Joint Center for Structural Genomics for the small model organism Thermotoga maritima (JCSG) (8,9). Assessment of the accuracy of methods for protein structure prediction, e.g. during the bi-annual CASP (Critical Assessment of Techniques for Protein Structure Prediction) experiments (10,11) or the automated EVA project (12), has demonstrated that comparative protein structure modelling is currently the most accurate technique for prediction of the 3D structure of proteins. During the CASP7 experiment, it became apparent that the best fully automated modelling methods have improved to a level where they challenge most human predictors in producing the most accurate models (13–15). Nowadays, comparative protein structure models are often sufficiently accurate to be employed for a wide spectrum of biomedical applications, such as structure based drug design (16–20), functional characterization of diverse members of a protein family (21), or rational protein engineering, e.g. the humanization of therapeutic antibodies, or to study functional properties of proteins (22–26).

Here, we describe the SWISS-MODEL Repository, a database of annotated protein structure models generated by the SWISS-MODEL Pipeline, and a set of associated web-based services that facilitate protein structure modelling and assessment. We emphasize the improvements of the SWISS-MODEL Repository which have been implemented since our last report (27). These include a new pipeline for template selection, the integration with interactive tools in the SWISS-MODEL Workspace, the programmatic access via DAS (distributed annotation system) (28), the implementation of a reference frame for protein sequences based on md5 cryptographic hashes, and the integration with the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base (29,30).

REPOSITORY CONTENTS, ACCESS AND INTERFACE

Graphical user web interface

The web interface at http://swissmodel.expasy.org/repository/ provides the main entry point to the SWISS-MODEL Repository. Models for specific proteins can be queried using different database accession codes (e.g. UniProt AC and ID, GenBank, IPI, Refseq) or directly with the protein amino acid sequence (or fragments thereof, e.g. for a specific domain). For a given target protein, a graphical overview illustrating the segments for which models (or experimental structures) are available is shown (Figure 1). Functional and domain annotation for the target protein is retrieved dynamically in real time using web service protocols to ensure that the annotation information is up-to-date. UniProt annotation of the target protein is retrieved via REST queries (http://www.uniprot.org). Structural domains in the target protein are annotated by PFAM domain assignment (41), which is retrieved dynamically by querying the InterPro (42) database using the DAS protocol (28). The md5-based reference frame for target proteins allows to update the database accession mappings in between modelling release cycles. This ensures that cross references with functional annotation resources such as InterPro correspond to proteins of identical primary sequence, thereby avoiding commonly observed problems with incorrect cross-references as a result of instable accession codes or asynchronous updates of different data resources. Finally, for each model, a summary page provides information on the modelling process (template selection and alignment), model quality assessment by ANOLEA (36) and Gromos (35), and in page visualization of the structure using the Astex Viewer (43) plugin.

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Figure 1.

Typical view of a SWISS-MODEL Repository entry. For the UniProt entry {"type":"entrez-protein","attrs":{"text":"P53354","term_id":"205638829","term_text":"P53354"}}P53354, the α-amylase I (EC 3.2.1.1; 1,4-α-d-glucan glucanohydrolase) from Aedes aegypti (Yellowfever mosquito), a model covering the active amylase domain is shown, including information on the template structure used for model building, the target–template sequence alignment, and quality assessment of the model. Functional annotation such as PFAM domain structure and UniProt annotation of the protein sequence is retrieved dynamically. Links to SWISS-MODEL Workspace enable the user to run additional model quality assessment tools on the model, or search the template library for alternative template structures.

INTEROPERABILITY

FUTURE DIRECTIONS

SWISS-MODEL Repository will be updated regularly to reflect the growth of the sequence and structure databases. Future releases of SWISS-MODEL Repository will include models of oligomeric assemblies, as well as models including essential co-factors, metal ions and structural ligands. Structural clustering of the Swiss Model Template Library will also allow us to routinely include ensembles of models for such proteins, which undergo extensive domain movements.

CITATION

Users of SWISS-MODEL Repository are requested to cite this article in their publications.

FUNDING

The PSI SGKB Protein Model Portal was supported by the National Institutes of Health as a sub-grant with Fox Chase Cancer Center (3 P20 GM076222-02S1); as a sub-grant with Rutgers University, under Prime Agreement Award Number (3U54GM074958-04S2). SWISS-MODEL Workspace and Repository have been supported by the Swiss Institute of Bioinformatics (SIB). Funding for open access charges: Swiss Institute of Bioinformatics.

Conflict of interest statement. None declared.

ACKNOWLEDGEMENTS

REFERENCES