SWISS-MODEL Workspace

Category Proteomics>Protein Structure/Modeling Systems/Tools

Abstract SWISS-MODEL Workspace is an automated comparative protein modeling environment and 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 aims to build three-dimensional protein structure models using experimentally determined structures of related family members as templates. And, 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 hrs. 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.

SWISS-MODEL Workspace Homology modeling --

Each of the four (4) steps in homology modeling requires specialized software as well as access to up-to-date protein sequence and structure databases. The SWISS-MODEL Workspace integrates the software required for homology modeling and databases in an easy-to-use Web-based modeling environment.

The Workspace assists the user in building and evaluating protein homology models at different levels of complexity - depending on the difficulty of the individual modeling task. A highly automated modeling procedure with a minimum of user intervention is provided for modeling scenarios where highly similar structural templates are available.

For more complex modeling tasks where target and template have lower sequence similarity, expert users are given control over the several steps of model building to construct a protein model that is optimally adapted to their scientific problem.

Modeling can be performed from within a Web browser without the need for downloading, compiling and installing large program packages or databases.

The results of different modeling tasks are presented in a graphical summary. As quality evaluation is indispensable for a predictive method like homology modeling, every model is accompanied by several quality checks.

Main components of the SWISS-MODEL Workspace --

1) Tools for target sequence feature annotation -

Functional and structural domain annotation of the target sequence of interest is the first step toward the identification of a suitable template for building its three-dimensional model. Individual structural domains of multi-domain proteins often correspond to units of distinct molecular function.

Furthermore, the sensitivity of profile-based template detection methods can be enhanced when the search is performed at the domain level rather than searching the whole protein sequence.

IprScan, a PERL-based InterProScan utility, has been integrated into SWISS-MODEL Workspace for the analysis of the domain architecture of the target protein and the annotation of its functional features.

Prediction tools for secondary structure, disorder and transmembrane (TM) regions complement the tools for protein sequence analysis and aid the selection of suitable modeling templates for specific regions of the target proteins.

In the twilight zone of sequence alignments, applying secondary structure prediction to the protein of interest may help decide whether a putative template shares essential structural features. Intrinsically unstructured regions in proteins have been associated with numerous important biological cellular functions, from cell signaling to transcriptional regulation;

Several examples of such disordered regions undergoing the transition to an ordered state upon binding their ligand proteins have been reported. Prediction of disordered and transmembrane regions, therefore complement the analysis of protein domain boundaries and functional annotation of the target protein.

2) Tools for template identification -

The SWISS-MODEL Workspace provides a set of increasingly sensitive sequence-based search methods for template detection that are applied depending on the evolutionary divergence between the target protein and the closest structurally characterized template protein.

Close homologs of the target can be identified using a gapped Basic Local Alignment Search Tool (BLAST) query against the SWISS-MODEL Template Library (SMTL).

When No closely related templates are found, or can be identified only for some segments of the target protein, more sensitive approaches for detecting evolutionary relationships are provided.

• a) In the iterative profile BLAST approach, which was initially introduced as Protein Data Base (PDB)-Blast by Godzik and coworkers, a profile for the target sequence is compiled from homologous sequences by iterative searches of the non-redundant protein database (NR database) and used subsequently to search SMTL for homologous structures.
• b) Alternatively, to detect more distantly related template structures, a Hidden Markov Model (HMM) for the target sequence is built on the basis of a multiple sequence alignment, similarly to the profile BLAST approach discussed above.

The HMM for the target sequence is subsequently used to search against the template library of HMMs generated for a non-redundant set of the sequences of the SMTL template library culled at 70% sequence identity. HMM building, calibration and library searches are performed using the HHSearch software package.

3) Modeling -

• a) Automated mode - If the alignment between the target and the template sequences displays a sufficiently high similarity, a fully automated homology modeling approach can be applied. As a rule of thumb, automated sequence alignments are sufficiently reliable when target and template share more than 50% of sequence identity.
• Submissions in ‘Automated mode’ require only the amino-acid sequence or the UniProt accession code of the target protein as input data. The hierarchical approach for template detection of the modeling pipeline will automatically select suitable templates on the basis of a BLAST search or using an adapted sequence-to-HMM comparison HHSearch protocol.
• In cases where several similar template structures are available, the automated template selection will favor high-resolution template structures with good-quality assessment. Optionally, a specific template from the SMTL template library can be specified.
• b) Alignment mode - For more distantly related target and template sequences, the number of errors in automated sequence alignments increases. This poses a major problem for automated homology modeling, as current methods are Not capable of recovering from an incorrect input alignment. In many molecular biology projects, multiple sequence alignments are often the result of extensive theoretical and experimental exploration of a family of proteins.
• Such alignments can be used for comparative modeling using the ‘Alignment mode’ if at least one of the member sequences represents a protein for which the three-dimensional structure is known. The ‘Alignment mode’ allows the user to test several alternative alignments and evaluate the quality of the resulting models to achieve an optimal result.
• c) Project mode - In the so-called ‘twilight zone’ of sequence alignments, when the sequence identity between target and template is below 30%, it is advisable to visually inspect and manually edit the target-template alignment. This will lead to a significant improvement of the quality of the resulting model.

The program DeepView (Swiss-PdbViewer) can be used to display, analyze and manipulate modeling projects. DeepView project files contain one or more superposed template structures and the alignment between the target and template(s).

Project files are also generated by the workspace template selection tools and are the default output format of the modeling pipeline. Project files with modified alignments can then be saved to disk and submitted as ‘Project mode’ to the workspace for model building by the SWISS-MODEL pipeline (workflow), thereby giving the user full control over essential modeling parameters:

Several template structures can be compared simultaneously to identify structurally conserved and variable regions, and select the most suitable template. The placement of insertions and deletions in the target-template alignment can be visualized in their structural context and adjusted accordingly.

4) Protein structure assessment and model quality estimation -

The percentage of sequence identity between target and template is generally accepted as a reasonable first estimate of the quality of a model. However, the accuracy of individual models may vary significantly from the expected average quality due to suboptimal target-template alignments, low template quality, structural flexibility or inaccuracies introduced by the modeling program. Individual assessment of each model is therefore essential.

As a global indicator of the quality of a given model, the results of QMEAN, a composite scoring function for model quality estimation, and DFIRE, an all-atom distance-dependent statistical potential, are provided in the SWISS-MODEL Workspace.

However, a good global score does Not guarantee that important functional sites of a protein have been modeled correctly. Therefore, tools for local model quality estimates are included: graphical plots of ANOLEA mean force potential, GROMOS empirical force field energy and the Neural Network-based approach ProQres are provided as indicators for local model quality.

ProQres - ProQres is a Neural Network (NN) based predictor that based on a number of structural features predicts the quality of different parts of a protein model.

Finally, Whatcheck and Procheck reports enable the user to assess the conformational quality of both models and template structures.

System Requirements

Web-based and contact the manufacturer.

Manufacturer

• Protein Structure Bioinformatics group at the SIB
• SIB Swiss Institute of Bioinformatics
• And
• Biozentrum University of Basel
• Basel, Switzerland

Manufacturer Web Site SWISS-MODEL Workspace

Price Contact manufacturer.

G6G Abstract Number 20723

G6G Manufacturer Number 104292