Correlated mutations select misfolded from properly folded proteins

Abstract

Supplementary data are available at Bioinformatics online.

Forecasting residue–residue contact prediction accuracy

“…Prediction of residue-residue contacts from sequence information alone has been a challenge in protein structure bioinformatics for a long time (Gö bel et al, 1994). Most often such contacts are predicted to support modelling of the three dimensional structure of a protein (Bohr et al, 1993;Konopka et al, 2014;Saitoh et al, 1993;Skolnick et al, 1997;Vendruscolo et al, 1997), but other fields like protein interface prediction (Du et al, 2016;Gonz alez et al, 2013;Horn et al, 1998), protein structure alignment (Terashi and Takeda-Shitaka, 2015), or even experimental protein structure determination and validation (Olmea et al, 1999;Wozniak et al, 2017) can benefit from contact prediction too. The importance of residue-residue contact prediction is further underlined by the fact that it is one of the challenges in the bi-annual CASP (Critical Assessment of techniques for protein Structure Prediction) (Monastyrskyy et al, 2014) event since 1996 (Lesk, 1997).…”

Residue-residue contacts in modeling protein structure

“…The knowledge of even incomplete maps allows selecting misfolded from properly folded proteins [2]. We designed a regression model that forecasts the accuracy of contact prediction for individual proteins with an average error of 7 percentage points [3]. Contact prediction can be further raised by including machine learning methods and structural filters.…”

Correlated mutations distinguish misfolded and properly folded proteins

“…Unfortunately, the accuracy of DCA methods is on the order of 40% among the 100 strongest predicted contacts, which is insufficient for ab initio protein structure reconstruction. However, the results of DCA can support protein structure reconstruction in a different way.Our results show that DCA can indicate the best protein structure among its structural variants by the prediction of residue-residue contacts [3]. We counted the number of correctly predicted contacts within the strongest 100 DCA predictions for a set of obsolete PDB entries and their successors and for 22 proteins for which the Decoys 'R' Us database [4] provided properly folded and misfolded structures.…”

“…Our results show that DCA can indicate the best protein structure among its structural variants by the prediction of residue-residue contacts [3]. We counted the number of correctly predicted contacts within the strongest 100 DCA predictions for a set of obsolete PDB entries and their successors and for 22 proteins for which the Decoys 'R' Us database [4] provided properly folded and misfolded structures.…”

“…DCA correctly predicts significantly more contacts for properly folded structures than for misfolded ones. Our method works much better for structures determined with X-ray crystallography than with the NMR spectroscopy [3]. The method will not detect misfolded proteins per se, but when a protein structure experimentalist needs to choose between alternative folds for the same protein, DCA can help.…”