AbstractCrystallography and NMR system (CNS) is currently the de facto standard for fragment-free ab initio protein folding from inter-residue distance or contact maps. Despite its widespread use in protein structure prediction, CNS is a decade-old macromolecular structure determination system that was originally developed for solving macromolecular geometry from experimental restraints as opposed to predictive modeling driven by interaction map data. As such, the adaptation of the CNS experimental structure determination protocol for ab initio protein folding is intrinsically anomalous that may undermine the folding accuracy of computational protein structure prediction. In this paper, we propose a new CNS-free hierarchical structure modeling method called DConStruct for folding both soluble and membrane proteins driven by distance and contact information. Rigorous experimental validation shows that DConStruct attains much better reconstruction accuracy than CNS when tested with the same input contact map at varying contact thresholds. The hierarchical modeling with iterative self-correction employed in DConStruct scales at a much higher degree of folding accuracy than CNS with the increase in contact thresholds, ultimately approaching near-optimal reconstruction accuracy at higher-thresholded contact maps. The folding accuracy of DConStruct can be further improved by exploiting distance-based hybrid interaction maps at tri-level thresholding, as demonstrated by the better performance of our method in folding difficult free modeling targets from the 12th and 13th rounds of the Critical Assessment of techniques for protein Structure Prediction (CASP) experiments compared to several popular CNS- and fragment-based approaches, some of which even using much finer-grained distance maps than ours. Additional large-scale benchmarking shows that DConStruct can significantly improve the folding accuracy of membrane proteins compared to a CNS-based approach. These results collectively demonstrate the feasibility of greatly improving the accuracy of ab initio protein folding by optimally exploiting the information encoded in inter-residue interaction maps beyond what is possible by CNS.Author summaryPredicting the folded and functional 3-dimensional structure of a protein molecule from its amino acid sequence is of central importance to structural biology. Recently, promising advances have been made in ab initio protein folding due to the reasonably accurate estimation of inter-residue interaction maps at increasingly higher resolutions that range from binary contacts to finer-grained distances. Despite the progress in predicting the interaction maps, approaches for turning the residue-residue interactions projected in these maps into their precise spatial positioning heavily rely on a decade-old experimental structure determination protocol that is not suitable for predictive modeling. This paper presents a new hierarchical structure modeling method, DConStruct, which can better exploit the information encoded in the interaction maps at multiple granularities, from binary contact maps to distance-based hybrid maps at tri-level thresholding, for improved ab initio folding. Multiple large-scale benchmarking experiments show that our proposed method can substantially improve the folding accuracy for both soluble and membrane proteins compared to state-of-the-art approaches. DConStruct is licensed under the GNU General Public License v3 and freely available at https://github.com/Bhattacharya-Lab/DConStruct.
Ab initio simulations of protein-folding pathways by molecular dynamics with the united-residue model of polypeptide chains