Limits and potential of combined folding and docking using PconsDock.

Abstract

In the last decade, de novo protein structure prediction accuracy for individual proteins has improved significantly by utilising deep learning (DL) methods for harvesting the co-evolution information from large multiple sequence alignments (MSA). In CASP14, the best groups predicted the structure of most proteins with impressive accuracy. The same approach can, in principle, also be used to extract information about evolutionary-based contacts across protein-protein interfaces. However, most of the earlier studies have not used the latest DL methods for inter-chain contact distance prediction. This paper introduces a fold-and-dock method, PconsDock, based on predicted residue-residue distances with trRosetta. PconsDock can simultaneously predict the tertiary and quaternary structure of a protein pair, even when the structures of the monomers are not known. The straightforward application of this method to a standard dataset for protein-protein docking yielded limited success. However, using alternative methods for MSA generating allowed us to dock accurately significantly more proteins. We also introduced a novel scoring function, PconsDock, that accurately separates 98% of correctly and incorrectly folded and docked proteins. The average performance of the method is comparable to the use of traditional, template-based or ab initio shape-complementarity-only docking methods. However, no a priori structural information for the individual proteins is needed. Moreover, the results of conventional and fold-and-dock approaches are complementary, and thus a combined docking pipeline could increase overall docking success significantly. PconsDocck contributed to the best model for one of the CASP14 oligomeric targets, H1065.