About 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 from their amino acid sequences.
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
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
10th CASPs (2012),
ranked as the No 1 server in CASP7 and CASP8. In CASP9 and CASP10,
I-TASSER server and
QUARK (another server
from our lab) were ranked as No 1 and No 2 servers, respectively.
The detailed rank results can be seen
here for CASP7,
Figure 2 shows histograms of the Z-score of GDT-TS
scores of all servers in CASP7 (68 servers), CASP8 (72 servers), CASP9 (81 servers),
and CASP9 (72 servers).
Figure 2. Histogram of Z-scores of all server groups at CASP7,
CASP8, CASP9 and CASP10.
Figure 3 is a summary of COFACTOR, a component of I-TASSER server, in the function
prediction section of CASP9, where COFACTOR was registered as "I-TASSER_FUNCTION" and
"Zhang" in the server and human prediction sections, respectively. The picture was
taken from the presentation by the CASP9 assessor Dr. T Schwede, see
Mean MCC Z-scores of the best ten groups in the Function Prediction in CASP9.
What are the output of the I-TASSER server if you submit a seqeunce?
The output of the I-TASSER server include:
An illustrative example of the I-TASSER output can be seen from
- 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
- Predicted solvent accessibility
- Top 10 threading alignment from LOMETS
- Top 10 proteins in PDB which are structurally closest to the predicted models
- Predicted Enzyme Classification 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
How to use known information (e.g. templates and function) to improve I-TASSER modeling?
If users know some information about the structure of the modeled proteins,
the information can be conveniently uploaded to the I-TASSER server.
These information can significantly improve the quality of structural and
The I-TASSER server currently accepts two types of user-specified restraints:
(1) inter-residue contant and distance restraints;
The server provides 4 convenient options to assign the restraints:
(2) template structures and template-target alignments.
Please refer to adding restraints to I-TASSER modeling to view more detail illustrations.
- Assign contact/distance restraints: If you know what atom pairs should be in
contact or in some distances, you can use this option to upload a text file
including the contact and/or distance information of atom pairs.
- Specify template without alignment: If you want I-TASSER to use a specific
PDB structure as a template, you can use this option specify the PDB structure.
You only need to type in the PDBID:ChainID, e.g. 1wor:A without specifying
the target-template alignments. If the chain information is not present in
the PDB file, indicate the ChainID using "_". I-TASSER will first fetch the
structure from the PDB library and then generate the target-template alignment
based on our in-house alignment tool, MUSTER.
- Specify template without alignment: You can actually use any 3D structure
as the template, which does not necessary exist in the PDB library. In this
case, you can use this option to upload the 3D structure. This structure file
must be in the standard PDB format. You do not need to input the
target-template alignments. I-TASSER will generate target-template
alignment based on our in-house alignment tool, MUSTER.
- Specify template with alignment: This option allows you (usually the
advanced users) to specify both template structure and the target-template
Can I exclude some proteins from the I-TASSER template library?
I-TASSER needs templates to generate high-resolution structure predictions.
In general, excluding close templates will decrease the quality of the I-TASSER modeling.
However, users can exclude some templates from the I-TASSER template library for
some special purposes (e.g. knowning some templates are different from target, or
benchmark testing of the current algorithms).
The I-TASSER server accept two ways of template excludings:
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 longer time. The time also depends on the protein
size and a smaller protein takes shorter 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 servers do not attempt to refine the threading models, the response
time is faster than the I-TASSER server.
You are requested to cite following articles when you use the I-TASSER server:
Y Zhang. I-TASSER server for protein 3D structure prediction.
BMC Bioinformatics, vol 9, 40 (2008).
(download the PDF file).
A Roy, A Kucukural, Y Zhang. I-TASSER: a unified platform
for automated protein structure and function prediction.
Nature Protocols, 5: 725-738 (2010)
(download the PDF file)
The I-TASSER server is in active development with the goal to
provide the most accurate protein structure and function predictions
using the state-of-the-art methodologies. Please help us achieve
the goal by sending your questions, feedback, and comments to
I-TASSER Message Board