Correlated mutations select misfolded from properly folded proteins

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The recently developed direct coupling analysis (DCA) method has greatly improved the accuracy with which residue-residue contacts can be predicted from multiple sequence alignments. Contact prediction accuracy, though, is still often not sufficient for complete ab initio protein structure prediction. DCA can, however, support protein structure studies in several ways.


We show that DCA can select the better structure from among properly folded and misfolded variants. This idea was tested by comparing obsolete PDB files with their more correctly folded successors and by the comparison of structures with deliberately misfolded decoy models from the Decoys ′R′ Us database. The DCA method systematically predicts more contacts for properly folded structures than for misfolded ones. The method works much better for X-ray structures than for NMR structures.

Availability and Implementation:

All data are available from and


Supplementary information:

Supplementary data are available at Bioinformatics online.

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