Protein structure homology modelling has become a routine technique to generate 3D models for proteins when experimental structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modelling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estimation for selection of the most suitable templates and provides estimates of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.

SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) is a database of 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms. Regular updates ensure that target coverage is complete, that models are built using the most recent sequence and template structure databases, and that improvements in the underlying modelling pipeline are fully utilised. As of September 2008, the database contains 3.4 million entries for 2.7 million different protein sequences from the UniProt database. SWISS-MODEL Repository allows the users to assess the quality of the models in the database, search for alternative template structures, and to build models interactively via SWISS-MODEL Workspace (http://swissmodel.expasy.org/workspace/). Annotation of models with functional information and cross-linking with other databases such as the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base facilitates the navigation between protein sequence and structure resources.

Homology modeling aims to build three-dimensional protein structure models using experimentally determined structures of related family members as templates. SWISS-MODEL workspace is an integrated Web-based modeling expert system. For a given target protein, a library of experimental protein structures is searched to identify suitable templates. On the basis of a sequence alignment between the target protein and the template structure, a three-dimensional model for the target protein is generated. Model quality assessment tools are used to estimate the reliability of the resulting models. Homology modeling is currently the most accurate computational method to generate reliable structural models and is routinely used in many biological applications. Typically, the computational effort for a modeling project is less than 2 h. However, this does not include the time required for visualization and interpretation of the model, which may vary depending on personal experience working with protein structures.