Does inclusion of residue-residue contact information boost protein threading?

Abstract

Template-based modeling is considered as one of the most successful approaches for protein structure prediction. However, reliably and accurately selecting optimal template proteins from a library of known protein structures having similar folds as the target protein and making correct alignments between the target sequence and the template structures, a template-based modeling technique known as threading, remains challenging, particularly for non- or distantly-homologous protein targets. With the recent advancement in protein residue-residue contact map prediction powered by sequence co-evolution and machine learning, here we systematically analyze the effect of inclusion of residue-residue contact information in improving the accuracy and reliability of protein threading. We develop a new threading algorithm by incorporating various sequential and structural features, and subsequently integrate residue-residue contact information as an additional scoring term for threading template selection. We show that the inclusion of contact information attains statistically significantly better threading performance compared to a baseline threading algorithm that does not utilize contact information when everything else remains the same. Experimental results demonstrate that our contact based threading approach outperforms popular threading method MUSTER, contact-assisted ab initio folding method CONFOLD2, and recent state-of-the-art contact-assisted protein threading methods EigenTHREADER and map_align on several benchmarks. Our study illustrates that the inclusion of contact maps is a promising avenue in protein threading to ultimately help to improve the accuracy of protein structure prediction.