Increasing the accuracy of protein loop structure prediction with evolutionary constraints.

Abstract

Accurate prediction of loop structures remains challenging. This is especially true for long loops where the large conformational space and limited coverage of experimentally determined structures often leads to low accuracy. Co-evolutionary contact predictors, which provide information about the proximity of pairs of residues, have been used to improve whole-protein models generated through de novo techniques. Here we investigate whether these evolutionary constraints can enhance the prediction of long loop structures. As a first stage, we assess the accuracy of predicted contacts that involve loop regions. We find that these are less accurate than contacts in general. We also observe that some incorrectly predicted contacts can be identified as they are never satisfied in any of our generated loop conformations. We examined two different strategies for incorporating contacts, and on a test set of long loops (10 residues or more), both approaches improve the accuracy of prediction. For a set of 135 loops, contacts were predicted and hence our methods were applicable in 97 cases. Both strategies result in an increase in the proportion of near-native decoys in the ensemble, leading to more accurate predictions and in some cases improving the root-mean-square deviation of the final model by more than 3Å. Supplementary data are available at Bioinformatics online.