Improved Contact Predictions Using the Recognition of Protein Like Contact Patterns

Given sufficient large protein families, and using a global statistical inference approach, it is possible to obtain sufficient accuracy in protein residue contact predictions to predict the structure of many proteins. However, these approaches do not consider the fact that the contacts in a protein are neither randomly, nor independently distributed, but actually follow precise rules governed by the structure of the protein and thus are interdependent. Here, we present PconsC2, a novel method that uses a deep learning approach to identify protein-like contact patterns to improve contact predictions. A substantial enhancement can be seen for all contacts independently on the number of aligned sequences, residue separation or secondary structure type, but is largest for β-sheet containing proteins. In addition to being superior to earlier methods based on statistical inferences, in comparison to state of the art methods using machine learning, PconsC2 is superior for families with more than 100 effective sequence homologs. The improved contact prediction enables improved structure prediction.Author Summary: Here, we introduce a novel protein contact prediction method PconsC2 that, to the best of our knowledge, outperforms earlier methods. PconsC2 is based on our earlier method, PconsC, as it utilizes the same set of contact predictions from plmDCA and PSICOV. However, in contrast to PconsC, where each residue pair is analysed independently, the initial predictions are analysed in context of neighbouring residue pairs using a deep learning approach, inspired by earlier work. We find that for each layer the deep learning procedure improves the predictions. At the end, after five layers of deep learning and inclusion of a few extra features provides the best performance. An improvement can be seen for all types of proteins, independent on length, number of homologous sequences and structural class. However, the improvement is largest for β-sheet containing proteins. Most importantly the improvement brings for the first time sufficiently accurate predictions to some protein families with less than 1000 homologous sequences. PconsC2 outperforms as well state of the art machine learning based predictors for protein families larger than 100 effective sequences. PconsC2 is licensed under the GNU General Public License v3 and freely available from http://c2.pcons.net/.