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1. Improving protein tertiary structure prediction by deep learning and distance prediction in CASP14

   https://doi.org/10.1002/prot.26186  

   Liu, Jian ; Wu, Tianqi ; Guo, Zhiye ; Hou, Jie ; Cheng, Jianlin ( July 2021 , Proteins: Structure, Function, and Bioinformatics)

   Substantial progresses in protein structure prediction have been made by utilizing deep‐learning and residue‐residue distance prediction since CASP13. Inspired by the advances, we improve our CASP14 MULTICOM protein structure prediction system by incorporating three new components: (a) a new deep learning‐based protein inter‐residue distance predictor to improve template‐free (ab initio) tertiary structure prediction, (b) an enhanced template‐based tertiary structure prediction method, and (c) distance‐based model quality assessment methods empowered by deep learning. In the 2020 CASP14 experiment, MULTICOM predictor was ranked seventh out of 146 predictors in tertiary structure prediction and ranked third out of 136 predictors in inter‐domain structure prediction. The results demonstrate that the template‐free modeling based on deep learning and residue‐residue distance prediction can predict the correct topology for almost all template‐based modeling targets and a majority of hard targets (template‐free targets or targets whose templates cannot be recognized), which is a significant improvement over the CASP13 MULTICOM predictor. Moreover, the template‐free modeling performs better than the template‐based modeling on not only hard targets but also the targets that have homologous templates. The performance of the template‐free modeling largely depends on the accuracy of distance prediction closely related to the quality of multiple sequence alignments. The structural model quality assessment works well on targets for which enough good models can be predicted, but it may perform poorly when only a few good models are predicted for a hard target and the distribution of model quality scores is highly skewed. MULTICOM is available athttps://github.com/jianlin-cheng/MULTICOM_Human_CASP14/tree/CASP14_DeepRank3andhttps://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.

    

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2. Combination of deep neural network with attention mechanism enhances the explainability of protein contact prediction

   https://doi.org/10.1002/prot.26052  

   Chen, Chen ; Wu, Tianqi ; Guo, Zhiye ; Cheng, Jianlin ( February 2021 , Proteins: Structure, Function, and Bioinformatics)

   Deep learning has emerged as a revolutionary technology for protein residue‐residue contact prediction since the 2012 CASP10 competition. Considerable advancements in the predictive power of the deep learning‐based contact predictions have been achieved since then. However, little effort has been put into interpreting the black‐box deep learning methods. Algorithms that can interpret the relationship between predicted contact maps and the internal mechanism of the deep learning architectures are needed to explore the essential components of contact inference and improve their explainability. In this study, we present an attention‐based convolutional neural network for protein contact prediction, which consists of two attention mechanism‐based modules: sequence attention and regional attention. Our benchmark results on the CASP13 free‐modeling targets demonstrate that the two attention modules added on top of existing typical deep learning models exhibit a complementary effect that contributes to prediction improvements. More importantly, the inclusion of the attention mechanism provides interpretable patterns that contain useful insights into the key fold‐determining residues in proteins. We expect the attention‐based model can provide a reliable and practically interpretable technique that helps break the current bottlenecks in explaining deep neural networks for contact prediction. The source code of our method is available athttps://github.com/jianlin-cheng/InterpretContactMap.

    

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3. MULTICOM2 open-source protein structure prediction system powered by deep learning and distance prediction

   https://doi.org/10.1038/s41598-021-92395-6  

   Wu, Tianqi ; Liu, Jian ; Guo, Zhiye ; Hou, Jie ; Cheng, Jianlin ( June 2021 , Scientific Reports)

   Protein structure prediction is an important problem in bioinformatics and has been studied for decades. However, there are still few open-source comprehensive protein structure prediction packages publicly available in the field. In this paper, we present our latest open-source protein tertiary structure prediction system—MULTICOM2, an integration of template-based modeling (TBM) and template-free modeling (FM) methods. The template-based modeling uses sequence alignment tools with deep multiple sequence alignments to search for structural templates, which are much faster and more accurate than MULTICOM1. The template-free (ab initio or de novo) modeling uses the inter-residue distances predicted by DeepDist to reconstruct tertiary structure models without using any known structure as template. In the blind CASP14 experiment, the average TM-score of the models predicted by our server predictor based on the MULTICOM2 system is 0.720 for 58 TBM (regular) domains and 0.514 for 38 FM and FM/TBM (hard) domains, indicating that MULTICOM2 is capable of predicting good tertiary structures across the board. It can predict the correct fold for 76 CASP14 domains (95% regular domains and 55% hard domains) if only one prediction is made for a domain. The success rate is increased to 3% for both regular and hard domains if five predictions are made per domain. Moreover, the prediction accuracy of the pure template-free structure modeling method on both TBM and FM targets is very close to the combination of template-based and template-free modeling methods. This demonstrates that the distance-based template-free modeling method powered by deep learning can largely replace the traditional template-based modeling method even on TBM targets that TBM methods used to dominate and therefore provides a uniform structure modeling approach to any protein. Finally, on the 38 CASP14 FM and FM/TBM hard domains, MULTICOM2 server predictors (MULTICOM-HYBRID, MULTICOM-DEEP, MULTICOM-DIST) were ranked among the top 20 automated server predictors in the CASP14 experiment. After combining multiple predictors from the same research group as one entry, MULTICOM-HYBRID was ranked no. 5. The source code of MULTICOM2 is freely available athttps://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.

    

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4. A gated graph transformer for protein complex structure quality assessment and its performance in CASP15

   https://doi.org/10.1093/bioinformatics/btad203  

   Chen, Xiao ; Morehead, Alex ; Liu, Jian ; Cheng, Jianlin ( June 2023 , Bioinformatics)

   Proteins interact to form complexes to carry out essential biological functions. Computational methods such as AlphaFold-multimer have been developed to predict the quaternary structures of protein complexes. An important yet largely unsolved challenge in protein complex structure prediction is to accurately estimate the quality of predicted protein complex structures without any knowledge of the corresponding native structures. Such estimations can then be used to select high-quality predicted complex structures to facilitate biomedical research such as protein function analysis and drug discovery.

   In this work, we introduce a new gated neighborhood-modulating graph transformer to predict the quality of 3D protein complex structures. It incorporates node and edge gates within a graph transformer framework to control information flow during graph message passing. We trained, evaluated and tested the method (called DProQA) on newly-curated protein complex datasets before the 15th Critical Assessment of Techniques for Protein Structure Prediction (CASP15) and then blindly tested it in the 2022 CASP15 experiment. The method was ranked 3rd among the single-model quality assessment methods in CASP15 in terms of the ranking loss of TM-score on 36 complex targets. The rigorous internal and external experiments demonstrate that DProQA is effective in ranking protein complex structures.

   The source code, data, and pre-trained models are available at https://github.com/jianlin-cheng/DProQA.

    

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5. A deep dilated convolutional residual network for predicting interchain contacts of protein homodimers

   https://doi.org/10.1093/bioinformatics/btac063  

   Roy, Raj S. ; Quadir, Farhan ; Soltanikazemi, Elham ; Cheng, Jianlin ; Xu, ed., Jinbo ( February 2022 , Bioinformatics)

   Deep learning has revolutionized protein tertiary structure prediction recently. The cutting-edge deep learning methods such as AlphaFold can predict high-accuracy tertiary structures for most individual protein chains. However, the accuracy of predicting quaternary structures of protein complexes consisting of multiple chains is still relatively low due to lack of advanced deep learning methods in the field. Because interchain residue–residue contacts can be used as distance restraints to guide quaternary structure modeling, here we develop a deep dilated convolutional residual network method (DRCon) to predict interchain residue–residue contacts in homodimers from residue–residue co-evolutionary signals derived from multiple sequence alignments of monomers, intrachain residue–residue contacts of monomers extracted from true/predicted tertiary structures or predicted by deep learning, and other sequence and structural features.

   Tested on three homodimer test datasets (Homo_std dataset, DeepHomo dataset and CASP-CAPRI dataset), the precision of DRCon for top L/5 interchain contact predictions (L: length of monomer in a homodimer) is 43.46%, 47.10% and 33.50% respectively at 6 Å contact threshold, which is substantially better than DeepHomo and DNCON2_inter and similar to Glinter. Moreover, our experiments demonstrate that using predicted tertiary structure or intrachain contacts of monomers in the unbound state as input, DRCon still performs well, even though its accuracy is lower than using true tertiary structures in the bound state are used as input. Finally, our case study shows that good interchain contact predictions can be used to build high-accuracy quaternary structure models of homodimers.

   The source code of DRCon is available at https://github.com/jianlin-cheng/DRCon. The datasets are available at https://zenodo.org/record/5998532#.YgF70vXMKsB.

   Supplementary data are available at Bioinformatics online.

    

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