Predicting loop conformational ensembles

Motivation Protein function is often facilitated by the existence of multiple stable conformations. Structure prediction algorithms need to be able to model these different conformations accurately, and produce an ensemble of structures that represent a target’s conformational diversity rather than just a single state. Here, we investigate whether current loop prediction algorithms are capable of this. We use the algorithms to predict the structures of loops with multiple experimentally-determined conformations, and the structures of loops with only one conformation, and assess their ability to generate and select decoys that are close to any, or all, of the observed structures. Results We find that while loops with only one known conformation are predicted well, conformationally diverse loops are modelled poorly, and in most cases the predictions returned by the methods do not resemble any of the known conformers. Our results contradict the often-held assumption that multiple native conformations will be present in the decoy set, making the production of accurate conformational ensembles impossible, and hence indicating that current methodologies are not well suited to prediction of conformationally diverse, often functionally important protein regions.