iFC2: an integrated web-server for the improved prediction of protein fold type, structural class, and secondary structure content

doi:10.1038/nprot.2008.162

Method Article

iFC²: an integrated web-server for the improved prediction of protein fold type, structural class, and secondary structure content

https://doi.org/10.1038/nprot.2008.162

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Biochemistry

Computational biology and bioinformatics

protein structure

protein structure prediction

fold type

secondary structure

structural class

fold recognition

secondary structure content

Recent research resulted in the development of several 1D protein structure descriptors. They provide an important alternative for analysis/prediction of the protein structure/function. Numerous computational methods that provide accurate prediction of these descriptors from the protein sequence were proposed; they include secondary structure^1-5, secondary structure content^6-9, structural class^10-17, fold type^18-25, relative solvent accessibility^26-32, contact order and number^33-37, and residue depth³⁸. Recent work shows that the tertiary structure can be recovered from three 1D descriptors³⁹.

We developed a server that integrates predictions of several related descriptors including structural class¹⁷, fold type²³, and secondary structure content⁹. The knowledge of these three descriptors was applied in various areas including tertiary structure prediction⁴⁰, identification of domain boundaries⁴¹, analysis of protein interactions⁴² and prion proteins⁴³, discrimination of outer membrane proteins^44,45, and in prediction of secondary structure⁴⁶, coding and noncoding RNAs⁴⁷, folding and unfolding rates^48-52, folding transition-state position⁵³, DNA-binding sites⁵⁴, and enzyme proteins and their class^55,56. Our server, iFC² (Integrated prediction of Fold, Class, and Content), is the first to exploit relations between the three descriptors, which are used to develop a cross-evaluation procedure that improves their predictions. iFC² predictions provide higher quality than the predictions of the individual methods.

The server is located at http://biomine.ece.ualberta.ca/1D/1D.html.

A single or multiple (up to 10) protein sequences to be predicted should be provided in FASTA format.

The user needs a computer with access to Internet and a Web browser.

1| Enter query sequences.

Prepare one or several protein sequences for prediction. The iFC² server accepts at most 10 protein sequences each time. The input sequences should be in FASTA format.

2| Use the prediction server.

To use iFC² server, access the prediction page at http://biomine.ece.ualberta.ca/1D/1D.html. Enter the protein sequences into the “Enter protein sequence(s)” box. The sequence has to be provided in FASTA format and the user is allowed to enter up to 10 sequences at the time. The prediction will be executed sequentially and automatically for all entered sequences. The “Example” button fills the box with an example of FASTA formatted sequence. The “Reset” button clears the contents of the box.

3| Choose prediction task.

There are 4 options, see Figure 1. The user can either perform single prediction task, i.e., secondary structure content prediction with PSSC-core⁹, structural class prediction with SCEC¹⁷, and fold type prediction with PFRES²³, or (s)he can use the integrated iFC² server (by pressing on the ‘all methods’ button), which predicts the three targets at the same time. If iFC² server is chosen, the cross-evaluation will be performed automatically. After choosing the prediction task, the user should press “Start” button. In the case when sequences entered in the “Enter protein sequence(s)” box do not adhere to the FASTA format, an error window that describes the problem will be displayed and the user will be asked to correct the formatting.

4| Obtain the results.

After the prediction is done, the user can access the prediction results by pressing the “Show Results” button, or download the results in a comma-separated text format by pressing the “Download CSV File” button.

5| Interpret the results.

The results are displayed using a web page, see Figure 2. The page displays (from top to bottom) the input sequence, the secondary structure predicted with PSI-PRED¹, the fold type predicted by PFRES²³, the structural class predicted by SCEC¹⁷, the secondary structure contents predicted with PSSC-core⁹, and the cross-evaluation results. For the fold type prediction, the output is one the 26 fold types described in ²³. For the structural class prediction, the output is one of the four structural classes (all-, all-, /, and +). In the case of the secondary structure content prediction, the output is two real values which represent the helix and the strand contents, respectively. The cross-evaluation results include the secondary structure contents of helix and strand re-predicted by iFC² server (which is potentially different from the predictions of PSSC-core⁹), the output label provided by iFC² server which flags the prediction of SCEC as potentially correct or incorrect, and the label generated by iFC² server that annotates the prediction of PFRES as potentially correct or incorrect.

The computational time depends on the length of the sequence.

Execution of PSSC-core⁹ (for secondary structure content prediction) takes about 10s for a protein sequence consisting of 200 amino acids. Average time to run SCEC¹⁷ (for structural class prediction), PFRES²³ (for fold type prediction), and iFC² for a sequence of about 200 amino acids is about 2mins for each method.

If the server does not accept the input protein sequence for prediction, the error might be caused by one of the following reasons:

(1) Input sequence(s) is not in the FASTA format.

(2) Input sequence(s) is less than 30 AAs and such sequence is considered to be too short to constitute a complete protein domain.

(3) The input sequence(s) contains invalid characters. The valid single-letter characters for a protein sequence are ACDEFGHIKLMNPQRSTVWY.

(4) More than 10 sequences were entered.

The quality of predictions of PSSC-core⁹, SCEC¹⁷, and PFRES²³ is evaluated and discussed in the corresponding publications.

Independent tests of the cross-evaluation procedure of iFC² server show that:

(1) The MAE (mean absolute error) of helix and strand content predicted by iFC² server equal 0.085 and 0.049, respectively. The PCC (Pearson correlation coefficient) values equal 0.94 for the helix content prediction and 0.89 for the strand content prediction.

(2) iFC² server assigns “correct” labels for 79.3% of predictions made by SCEC¹⁷. Among these “correct” predictions, the accuracy of SCEC equals 98.2%, while the accuracy of SCEC for the predictions deemed as “incorrect” by iFC² server equals 14.6%.

(3) iFC² server labels 81.8% of the PFRES²³ predictions as “correct” and the accuracy of these predictions equals 71.8%. At the same time, the accuracy of predictions performed with PFRES for the sequences predicted by iFC² server as “incorrect” equals 38.5%.

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This work was supported in part by iCORE, Alberta Ingenuity Fund, and NSERC (Natural Sciences and Engineering Research Council of Canada).

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