SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information

Abstract

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/.

Figure 1.

Templates selection and visualization. (A) An interactive chart shows the relationship of detected templates in sequence-similarity space. The target protein is represented as filled red circle. Each template is displayed as a blue circle, where the thick blue arc indicates target coverage (the N-terminus of the target protein starts at the top of the circle, and ends in clockwise direction with the C-terminus to close the circle). The distance between different templates is proportional to the pairwise sequence similarity, i.e. evolutionarily closely related templates will be clustered together. (B) Clicking on a circle will display template-specific information. A group of similar templates can be also visualized and selected by hovering over a cluster of templates. (C) The superposed structures of the selected templates will be instantaneously displayed in 3D to visually inspect structural differences.

Figure 2.

Modelling results. (A) For each model, coordinates, target-template alignment, modelling log and quality estimation information are provided. Information about the oligomeric structure, ligands and cofactors is also provided. (B) The colouring of the target-template sequence alignment can be changed to another scheme by clicking on the option button (adjustable spanner icon). Changes are simultaneously reflected in the structural representation of the model. (C) Models displayed in the interactive viewer are initially coloured by model quality estimates assigned by QMEAN. This allows instantly discriminating regions of the model which are well or poorly modelled. Local estimates of the model quality based on the QMEAN scoring function are shown as per-reside plot (A) and as global score in relation to a set of high-resolution PDB structures (Z-score) (D).