DeepHelicon: Accurate prediction of inter-helical residue contacts in transmembrane proteins by residual neural networks

Abstract

Accurate prediction of amino acid residue contacts is an important prerequisite for generating high-quality 3D models of transmembrane (TM) proteins. While a large number of compositional, evolutionary, and structural properties of proteins can be used to train contact prediction methods, recent research suggests that coevolution between residues provides the strongest indication of their spatial proximity. We have developed a deep learning approach, DeepHelicon, to predict inter-helical residue contacts in TM proteins by considering only coevolutionary features. DeepHelicon comprises a two-stage supervised learning process by residual neural networks for a gradual refinement of contact maps, followed by variance reduction by an ensemble of models. We present a benchmark study of 12 contact predictors and conclude that DeepHelicon together with the two other state-of-the-art methods DeepMetaPSICOV and Membrain2 outperforms the 10 remaining algorithms on all datasets and at all settings. On a set of 44 TM proteins with an average length of 388 residues DeepHelicon achieves the best performance among all benchmarked methods in predicting the top L/5 and L/2 inter-helical contacts, with the mean precision of 87.42% and 77.84%, respectively. On a set of 57 relatively small TM proteins with an average length of 298 residues DeepHelicon ranks second best after DeepMetaPSICOV. DeepHelicon produces the most accurate predictions for large proteins with more than 10 transmembrane helices. Coevolutionary features alone allow to predict inter-helical residue contacts with an accuracy sufficient for generating acceptable 3D models for up to 30% of proteins using a fully automated modeling method such as CONFOLD2.