Protein function prediction in genomes: Critical assessment of coiled-coil predictions based on protein structure data

Abstract

Coiled-coil regions were among the first protein motifs described structurally and theoretically. The beauty and simplicity of the motif gives hope to detecting coiled-coil regions with reasonable accuracy and precision in any protein sequence. Here, we reevaluated the most commonly used coiled-coil prediction tools with respect to the most comprehensive reference data set available, the entire Protein Data Base (PDB), down to each amino acid and its secondary structure. Apart from the thirtyfold difference in number of predicted coiled-coils the tools strongly vary in their predictions, across structures and within structures. The evaluation of the false discovery rate and Matthews correlation coefficient, a widely used performance metric for imbalanced data sets, suggests that the tested tools have only limited applicability for large data sets. Coiled-coil predictions strongly impact the functional characterization of proteins, are used for functional genome annotation, and should therefore be supported and validated by additional information.

Distribution of disease-causing germline mutations in coiled-coils implies an important role of their N-terminal region

“…We found that DMs accumulate in heptad positions critical for the assembly of coiled-coils (in line with the findings published by Mohanasundaram et al 14 ), N-terminal parts of coiled-coils are more abundant in DMs, and mutations mostly affect homooligomeric coiled-coils. Interestingly, in recent analyses some coiled-coil prediction methods showed a rather low accuracy and their result is sometimes contradictory 17,18 , however, based on the agreement of the distribution of variations predicted by different methods, they show balanced performance on our dataset.…”