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1. Improving deep learning-based protein distance prediction in CASP14

   https://doi.org/10.1093/bioinformatics/btab355  

   Guo, Zhiye ; Wu, Tianqi ; Liu, Jian ; Hou, Jie ; Cheng, Jianlin ( May 2021 , Bioinformatics)

   Martelli, Pier Luigi (Ed.)

   Abstract Motivation Accurate prediction of residue-residue distances is important for protein structure prediction. We developed several protein distance predictors based on a deep learning distance prediction method and blindly tested them in the 14th Critical Assessment of Protein Structure Prediction (CASP14). The prediction method uses deep residual neural networks with the channel-wise attention mechanism to classify the distance between every two residues into multiple distance intervals. The input features for the deep learning method include co-evolutionary features as well as other sequence-based features derived from multiple sequence alignments (MSAs). Three alignment methods are used with multiple protein sequence/profile databases to generate MSAs for input feature generation. Based on different configurations and training strategies of the deep learning method, five MULTICOM distance predictors were created to participate in the CASP14 experiment. Results Benchmarked on 37 hard CASP14 domains, the best performing MULTICOM predictor is ranked 5th out of 30 automated CASP14 distance prediction servers in terms of precision of top L/5 long-range contact predictions (i.e. classifying distances between two residues into two categories: in contact (< 8 Angstrom) and not in contact otherwise) and performs better than the best CASP13 distance prediction method. The best performing MULTICOM predictor is also rankedmore »6th among automated server predictors in classifying inter-residue distances into 10 distance intervals defined by CASP14 according to the precision of distance classification. The results show that the quality and depth of MSAs depend on alignment methods and sequence databases and have a significant impact on the accuracy of distance prediction. Using larger training datasets and multiple complementary features improves prediction accuracy. However, the number of effective sequences in MSAs is only a weak indicator of the quality of MSAs and the accuracy of predicted distance maps. In contrast, there is a strong correlation between the accuracy of contact/distance predictions and the average probability of the predicted contacts, which can therefore be more effectively used to estimate the confidence of distance predictions and select predicted distance maps. Availability The software package, source code, and data of DeepDist2 are freely available at https://github.com/multicom-toolbox/deepdist and https://zenodo.org/record/4712084#.YIIM13VKhQM.« less
2. Improving fragment-based ab initio protein structure assembly using low-accuracy contact-map predictions

   https://doi.org/10.1038/s41467-021-25316-w  

   Mortuza, S. M. ; Zheng, Wei ; Zhang, Chengxin ; Li, Yang ; Pearce, Robin ; Zhang, Yang ( August 2021 , Nature Communications)

   Sequence-based contact prediction has shown considerable promise in assisting non-homologous structure modeling, but it often requires many homologous sequences and a sufficient number of correct contacts to achieve correct folds. Here, we developed a method, C-QUARK, that integrates multiple deep-learning and coevolution-based contact-maps to guide the replica-exchange Monte Carlo fragment assembly simulations. The method was tested on 247 non-redundant proteins, where C-QUARK could fold 75% of the cases with TM-scores (template-modeling scores) ≥0.5, which was 2.6 times more than that achieved by QUARK. For the 59 cases that had either low contact accuracy or few homologous sequences, C-QUARK correctly folded 6 times more proteins than other contact-based folding methods. C-QUARK was also tested on 64 free-modeling targets from the 13th CASP (critical assessment of protein structure prediction) experiment and had an average GDT_TS (global distance test) score that was 5% higher than the best CASP predictors. These data demonstrate, in a robust manner, the progress in modeling non-homologous protein structures using low-accuracy and sparse contact-map predictions.
3. DEEPCON: protein contact prediction using dilated convolutional neural networks with dropout

   https://doi.org/10.1093/bioinformatics/btz593  

   Adhikari, Badri ; Elofsson, ed., Arne ( July 2019 , Bioinformatics)

   Exciting new opportunities have arisen to solve the protein contact prediction problem from the progress in neural networks and the availability of a large number of homologous sequences through high-throughput sequencing. In this work, we study how deep convolutional neural networks (ConvNets) may be best designed and developed to solve this long-standing problem.

   With publicly available datasets, we designed and trained various ConvNet architectures. We tested several recent deep learning techniques including wide residual networks, dropouts and dilated convolutions. We studied the improvements in the precision of medium-range and long-range contacts, and compared the performance of our best architectures with the ones used in existing state-of-the-art methods. The proposed ConvNet architectures predict contacts with significantly more precision than the architectures used in several state-of-the-art methods. When trained using the DeepCov dataset consisting of 3456 proteins and tested on PSICOV dataset of 150 proteins, our architectures achieve up to 15% higher precision when L/2 long-range contacts are evaluated. Similarly, when trained using the DNCON2 dataset consisting of 1426 proteins and tested on 84 protein domains in the CASP12 dataset, our single network achieves 4.8% higher precision than the ensembled DNCON2 method when top L long-range contacts are evaluated.

   DEEPCON is available at https://github.com/badriadhikari/DEEPCON/.

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4. DeepDist: real-value inter-residue distance prediction with deep residual convolutional network

   https://doi.org/10.1186/s12859-021-03960-9  

   Wu, Tianqi ; Guo, Zhiye ; Hou, Jie ; Cheng, Jianlin ( December 2021 , BMC Bioinformatics)

   Abstract Background Driven by deep learning, inter-residue contact/distance prediction has been significantly improved and substantially enhanced ab initio protein structure prediction. Currently, most of the distance prediction methods classify inter-residue distances into multiple distance intervals instead of directly predicting real-value distances. The output of the former has to be converted into real-value distances to be used in tertiary structure prediction. Results To explore the potentials of predicting real-value inter-residue distances, we develop a multi-task deep learning distance predictor (DeepDist) based on new residual convolutional network architectures to simultaneously predict real-value inter-residue distances and classify them into multiple distance intervals. Tested on 43 CASP13 hard domains, DeepDist achieves comparable performance in real-value distance prediction and multi-class distance prediction. The average mean square error (MSE) of DeepDist’s real-value distance prediction is 0.896 Å 2 when filtering out the predicted distance ≥ 16 Å, which is lower than 1.003 Å 2 of DeepDist’s multi-class distance prediction. When distance predictions are converted into contact predictions at 8 Å threshold (the standard threshold in the field), the precision of top L/5 and L/2 contact predictions of DeepDist’s multi-class distance prediction is 79.3% and 66.1%, respectively, higher than 78.6% and 64.5% of its real-value distance prediction and the best resultsmore »in the CASP13 experiment. Conclusions DeepDist can predict inter-residue distances well and improve binary contact prediction over the existing state-of-the-art methods. Moreover, the predicted real-value distances can be directly used to reconstruct protein tertiary structures better than multi-class distance predictions due to the lower MSE. Finally, we demonstrate that predicting the real-value distance map and multi-class distance map at the same time performs better than predicting real-value distances alone.« less
5. Hybridized distance- and contact-based hierarchical structure modeling for folding soluble and membrane proteins

   https://doi.org/10.1371/journal.pcbi.1008753  

   Roche, Rahmatullah ; Bhattacharya, Sutanu ; Bhattacharya, Debswapna ( February 2021 , PLOS Computational Biology)

   Kolodny, Rachel (Ed.)

   Crystallography and NMR system (CNS) is currently a widely used method 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 bettermore »performance of our method in folding free modeling targets from the 12th and 13th rounds of the Critical Assessment of techniques for protein Structure Prediction (CASP) experiments compared to popular CNS- and fragment-based approaches and energy-minimization protocols, 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.« less