Critical evaluation of in silico methods for prediction of coiled-coil domains in proteins

Abstract

Coiled-coils refer to a bundle of helices coiled together like strands of a rope. It has been estimated that nearly 3% of protein-encoding regions of genes harbour coiled-coil domains (CCDs). Experimental studies have confirmed that CCDs play a fundamental role in subcellular infrastructure and controlling trafficking of eukaryotic cells. Given the importance of coiled-coils, multiple bioinformatics tools have been developed to facilitate the systematic and high-throughput prediction of CCDs in proteins. In this article, we review and compare 12 sequence-based bioinformatics approaches and tools for coiled-coil prediction. These approaches can be categorized into two classes: coiled-coil detection and coiled-coil oligomeric state prediction. We evaluated and compared these methods in terms of their input/output, algorithm, prediction performance, validation methods and software utility. All the independent testing data sets are available at http://lightning.med.monash.edu/coiledcoil/. In addition, we conducted a case study of nine human polyglutamine (PolyQ) disease-related proteins and predicted CCDs and oligomeric states using various predictors. Prediction results for CCDs were highly variable among different predictors. Only two peptides from two proteins were confirmed to be CCDs by majority voting. Both domains were predicted to form dimeric coiled-coils using oligomeric state prediction. We anticipate that this comprehensive analysis will be an insightful resource for structural biologists with limited prior experience in bioinformatics tools, and for bioinformaticians who are interested in designing novel approaches for coiled-coil and its oligomeric state prediction.

Keywords: coiled-coil; oligomeric state; polyglutamine; prediction.

Figure 1.

Examples of coiled-coil oligomeric states. (A) Antiparallel dimer (PDB Accession: 1I49 [4]). (B) Parallel dimer (PDB Accession: 1D7M [5]). (C) Trimer (PDB Accession: 1HTM [6]). (D) Tetramer (PDB Accession: 1TXP [7]). A colour version of this figure is available at BIB online: http://bib.oxfordjournals.org.

Figure 2.

Performance comparison of coiled-coils with non-canonical heptad registers between RFCoil, SCORER 2.0, PrOCoil and LOGICOIL on the independent test. (A) ROC curves and the 95% confidence intervals for parallel dimeric and trimeric coiled-coils with length ≥8 amino acids. (B) ROC curves and the 95% confidence intervals for parallel dimeric and trimeric coiled-coils with length ≥15 amino acids. (C) ROC curves and the 95% confidence intervals of LOGICOIL for pairwise oligomeric state prediction with coiled-coils with length ≥15 residues. A colour version of this figure is available at BIB online: http://bib.oxfordjournals.org.

Figure 3.

Performance comparison of coiled-coils without non-canonical heptad registers between RFCoil, SCORER 2.0, PrOCoil and LOGICOIL on the independent test. (A) ROC curves and the 95% confidence intervals for parallel dimeric and trimeric coiled-coils with length ≥8 amino acids. (B) ROC curves and the 95% confidence intervals for parallel dimeric and trimeric coiled-coils with length ≥15 amino acids. (C) ROC curves and the 95% confidence intervals of LOGICOIL for pairwise oligomeric state prediction with coiled-coils with length ≥15 residues. A colour version of this figure is available at BIB online: http://bib.oxfordjournals.org.

Figure 4.

ROC curves and the 95% confidence intervals of Multcoil2 and other predictors for parallel dimeric and trimeric coiled-coil prediction. A colour version of this figure is available at BIB online: http://bib.oxfordjournals.org.

Figure 5.

Performance comparison of CCD predictors. (A) ROC curves and the 95% confidence intervals of different predictors for identifying coiled-coil domains. (B) ROC curves and the 95% confidence intervals of different predictors, showing the consistency between the predicted CCDs and those annotated by SOCKET based on the protein structures. A colour version of this figure is available at BIB online: http://bib.oxfordjournals.org.