I-TASSER server for protein structure and function prediction

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About I-TASSER server

What is I-TASSER server?

I-TASSER server is an internet service for protein structure and function predictions. It allows acedemic users to automatically generate high-quality predictions of 3D structure and biological function of protein molecules.

How does I-TASSER generate structure and function predictions?

When users submit an amino acid sequence, the server first tries to retrieve template proteins of similar folds (or super-secondary structures) from the PDB library by LOMETS, a locally installed meta-threading approach.

In the second step, the continuous fragments excised from the PDB templates are reassembled into full-length models by replica-exchange Monte Carlo simulations with the threading unaligned regions (mainly loops) built by ab initio modeling. In cases where no appropriate template is identified by LOMETS, I-TASSER will build the whole structures by ab initio modeling. The low free-energy states are identified by SPICKER through clustering the simulation decoys.

In the third step, the fragment assembly simulation is performed again starting from the SPICKER cluster centroids, where the spatial restrains collected from both the LOMETS templates and the PDB structures by TM-align are used to guide the simulations. The purpose of the second iteration is to remove the steric clash as well as to refine the global topology of the cluster centroids. The decoys generated in the second simulations are then clustered and the lowest energy structures are selected. The final full-atomic models are obtained by REMO which builds the atomic details from the selected I-TASSER decoys through the optimization of the hydrogen-bonding network (see Figure 1).

Figure 1. I-TASSER protocol for protein structure and function prediction.

For predicting the biological function of the protein (the last column at Figure 1), the I-TASSER server matches the predicted 3D models to the proteins in 3 independent libraries which consist of proteins of known enzyme classification (EC) number, gene ontology (GO) vocabulary, and ligand-binding sites. The final results of function predictions are deduced from the consensus of top structural matches with the function scores calculated based on the confidence score of the I-TASSER structural models, the structural similarity between model and templates as evaluated by TM-score, and the sequence identity in the structurally aligned regions [A similar approach to structure-based function annotation was proposed by Brylinski and Skolnick (PNAS 2008. 205:129) who tried to match the target structures on the threading templates. Here the I-TASSER server matches the target models on all template proteins in the libraries].

What are the performances of I-TASSER server compared with other methods?

CASP (or Critical Assessment of Techniques for Protein Structure Prediction) is a community-wide experiment for testing the state-of-the-art of protein structure predictions which takes place every two years since 1994. The experiment (often referred as a competition) is strictly blind because the structures of testing proteins are unknown to the predictors.

The I-TASSER server (as "Zhang-Server") participated in the Server Section of 7th and 8th CASPs in 2006 and 2008, and was ranked as the No 1 server in both competitions (the full rank results can be seen here for CASP7 and CASP8). Figure 2 shows histograms of the Z-score of GDT-TS scores of all servers in CASP7 (68 servers) and CASP8 (81 servers).

Figure 2. Histogram of Z-score at CASP7 and CASP8.

What are the output of the I-TASSER server if you submit a seqeunce?

The output of the I-TASSER server include:

Up to five full-length atomic models (ranked based on cluster density)
Estimated accuracy of the predicted models (including a confidence score of all models, and predicted TM-score and RMSD for the first model)
GIF images of the predicted models
Predicted secondary structures
Top 10 threading alignment from LOMETS
Top 10 proteins in PDB which are structurally closest to the predicted models
Predicted EC numbers and the confidence score
Predicted GO terms and the confidence score
Predicted ligand-binding sites and the confidence score
An image of the predicted ligand-binding sites

An illustrative example of the I-TASSER output can be seen from here.

What is new (since January, 2009)?

2009/01/10: In addition to the predicted I-TASSER models, two other predictions were added in the output page:
- Threading templates and the alignments which were identified by LOMETS and used by I-TASSER as initial input.
- Structural homologs of I-TASSER which are identified by structural alignment program TM-align through the PDB library.
2009/03/16: Structure-based function predictions were developed based on the global and local match of the predicted 3D models with the known homolog and analog proteins. The function predictions include ligand binding site, enzyme commission, and gene ontology.
2009/07/20: Added features to allow users to assign external restraints to guide the I-TASSER structural modeling. The user-specified information includes:
- Residue-residue contact/distance information
- Specific template structures and alignments
More details can be found at How to Add Restraints to I-TASSER Modeling.
2009/10/15: A new interface Search was added to allow users to search targets and predictions through the I-TASSER database.
2009/10/17: A timer was added to the Queue page to allow users track the implementation time of their targets. A number of other changes were made in the Queue page for improving the efficiency of retrieving I-TASSER output data.
2009/11/15: Molecular Dynamic simulations were implemented on I-TASSER models for removing steric clashes of side-chain atoms and for further refining rotamer conformations.

How long does it take for I-TASSER to generate the predictions for your protein?

It usually takes server hours to 1~2 days from submitting a sequence to receiving the prediction results. But if too many sequences are accumulated in the queue, the procedure may take a much longer time. The time also depends on the protein size and a smaller protein takes short time than a larger protein.

Currently, the major time consuming part in the I-TASSER protocol is the structural refinement assembly simulations. For those users who want a quicker reponse or those who do not need a refined models, we recommend them to use our LOMETS (meta-server) or MUSTER (single-server fold-recognition). Because these two server do not attempt to refine the threading models, the response time is faster than the I-TASSER server.