scholarly journals Protein tertiary structure modeling driven by deep learning and contact distance prediction in CASP13

2019 ◽  
Author(s):  
Jie Hou ◽  
Tianqi Wu ◽  
Renzhi Cao ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Structure Modeling ◽  
Contact Distance ◽  
Protein Model ◽  
Template Free ◽  
Distance Prediction

AbstractPrediction of residue-residue distance relationships (e.g. contacts) has become the key direction to advance protein tertiary structure prediction since 2014 CASP11 experiment, while deep learning has revolutionized the technology for contact and distance distribution prediction since its debut in 2012 CASP10 experiment. During 2018 CASP13 experiment, we enhanced our MULTICOM protein structure prediction system with three major components: contact distance prediction based on deep convolutional neural networks, contact distance-driven template-free (ab initio) modeling, and protein model ranking empowered by deep learning and contact prediction, in addition to an update of other components such as template library, sequence database, and alignment tools. Our experiment demonstrates that contact distance prediction and deep learning methods are the key reasons that MULTICOM was ranked 3rd out of all 98 predictors in both template-free and template-based protein structure modeling in CASP13. Deep convolutional neural network can utilize global information in pairwise residue-residue features such as co-evolution scores to substantially improve inter-residue contact distance prediction, which played a decisive role in correctly folding some free modeling and hard template-based modeling targets from scratch. Deep learning also successfully integrated 1D structural features, 2D contact information, and 3D structural quality scores to improve protein model quality assessment, where the contact prediction was demonstrated to consistently enhance ranking of protein models for the first time. The success of MULTICOM system in the CASP13 experiment clearly shows that protein contact distance prediction and model selection driven by powerful deep learning holds the key of solving protein structure prediction problem. However, there are still major challenges in accurately predicting protein contact distance when there are few homologous sequences to generate co-evolutionary signals, folding proteins from noisy contact distances, and ranking models of hard targets.

scholarly journals MULTICOM2: an open-source protein structure prediction system powered by deep learning and distance prediction

2021 ◽  
Author(s):  
Tianqi Wu ◽  
Jian Liu ◽  
Zhiye Guo ◽  
Jie Hou ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Open Source ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Modeling Method ◽  
Structure Modeling ◽  
Prediction System ◽  
Template Free

Abstract 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 at https://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.

scholarly journals MULTICOM2 open-source protein structure prediction system powered by deep learning and distance prediction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianqi Wu ◽  
Jian Liu ◽  
Zhiye Guo ◽  
Jie Hou ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Open Source ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Modeling Method ◽  
Structure Modeling ◽  
Prediction System ◽  
Template Free

AbstractProtein 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 at https://github.com/multicom-toolbox/multicom/tree/multicom_v2.0.

scholarly journals Improving protein tertiary structure prediction by deep learning and distance prediction in CASP14

2021 ◽  
Author(s):  
Jian Liu ◽  
Tianqi Wu ◽  
Zhiye Guo ◽  
Jie Hou ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Model Quality ◽  
Tertiary Structure Prediction ◽  
Model Quality Assessment ◽  
Template Free ◽  
Distance Prediction ◽  
Protein Tertiary Structure Prediction

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 in the three main aspects: (1) a new deep-learning based protein inter-residue distance predictor (DeepDist) to improve template-free (ab initio) tertiary structure prediction, (2) an enhanced template-based tertiary structure prediction method, and (3) distance-based model quality assessment methods empowered by deep learning. In the 2020 CASP14 experiment, MULTICOM predictor was ranked 7th out of 146 predictors in protein tertiary structure prediction and ranked 3rd out of 136 predictors in inter-domain structure prediction. The results of MULTICOM 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. The performance of template-free tertiary structure prediction largely depends on the accuracy of distance predictions that is closely related to the quality of multiple sequence alignments. The structural model quality assessment works reasonably well on targets for which a sufficient number of good models can be predicted, but 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.

scholarly journals Improving protein tertiary structure prediction by deep learning and distance prediction in CASP14

2021 ◽  
Author(s):  
Jian Liu ◽  
Tianqi Wu ◽  
Zhiye Guo ◽  
Jie Hou ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Model Quality ◽  
Tertiary Structure Prediction ◽  
Model Quality Assessment ◽  
Template Free ◽  
Distance Prediction ◽  
Protein Tertiary Structure Prediction

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 in three main aspects: (1) a new deep learning based protein inter-residue distance predictor (DeepDist) to improve template-free (ab initio) tertiary structure prediction, (2) an enhanced template-based tertiary structure prediction method, and (3) distance-based model quality assessment methods empowered by deep learning. In the 2020 CASP14 experiment, MULTICOM predictor was ranked 7th out of 146 predictors in protein tertiary structure prediction and ranked 3rd out of 136 predictors in inter-domain structure predic-tion. The results of MULTICOM 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. The performance of template-free tertiary structure prediction largely depends on the accuracy of distance pre-dictions that is closely related to the quality of multiple sequence alignments. The structural model quality assessment works reasonably well on targets for which a sufficient number of good models can be predicted, but 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.

scholarly journals Study of Real-Valued Distance Prediction For Protein Structure Prediction with Deep Learning

2020 ◽  
Author(s):  
Jin Li ◽  
Jinbo Xu
Keyword(s):  
Protein Structure ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
3D Structure ◽  
Prediction Method ◽  
Structure Modeling ◽  
Contact Prediction ◽  
Real Value ◽  
3D Structure Modeling ◽  
Distance Prediction

AbstractInter-residue distance prediction by deep ResNet (convolutional residual neural network) has greatly advanced protein structure prediction. Currently the most successful structure prediction methods predict distance by discretizing it into dozens of bins. Here we study how well real-valued distance can be predicted and how useful it is for 3D structure modeling by comparing it with discrete-valued prediction based upon the same deep ResNet. Different from the recent methods that predict only a single real value for the distance of an atom pair, we predict both the mean and standard deviation of a distance and then employ a novel method to fold a protein by the predicted mean and deviation. Our findings include: 1) tested on the CASP13 FM (free-modeling) targets, our real-valued distance prediction obtains 81% precision on top L/5 long-range contact prediction, much better than the best CASP13 results (70%); 2) our real-valued prediction can predict correct folds for the same number of CASP13 FM targets as the best CASP13 group, despite generating only 20 decoys for each target; 3) our method greatly outperforms a very new real-valued prediction method DeepDist in both contact prediction and 3D structure modeling; and 4) when the same deep ResNet is used, our real-valued distance prediction has 1-6% higher contact and distance accuracy than our own discrete-valued prediction, but less accurate 3D structure models.

scholarly journals ROPIUS0: A deep learning-based protocol for protein structure prediction and model selection and its performance in CASP14

2021 ◽  
Author(s):  
Mindaugas Margelevicius
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Model Selection ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Homologous Proteins ◽  
Tertiary Structure Prediction ◽  
Direct Use ◽  
Selection Of

A protocol ROPIUS0 for protein structure prediction and model selection is presented. At the core of the ROPIUS0 protocol is the deep learning module developed for the selection of protein structural models. It is shown that the direct use of predicted inter-residue distances may be sufficient to discriminate between correct and incorrect protein folds, considering only a small fraction of predicted distances. Having finished the latest CASP14 prediction season, a ROPIUS0 variant based on model selection ranks 13th in the category of tertiary structure prediction. Its performance is on par with top-performing automated prediction servers when tested on the CASP13 dataset. The results suggest ways to improve searching for structurally similar and homologous proteins without considerably increasing speed.

scholarly journals A fully open-source framework for deep learning protein real-valued distances

2020 ◽  
Author(s):  
Badri Adhikari
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Training Data ◽  
Learning Models ◽  
Web Browser ◽  
Fast Development ◽  
Protein Distance ◽  
Distance Prediction

AbstractAs deep learning algorithms drive the progress in protein structure prediction, a lot remains to be studied at this emerging crossway of deep learning and protein structure prediction. Recent findings show that inter-residue distance prediction, a more granular version of the well-known contact prediction problem, is a key to predict accurate models. We believe that deep learning methods that predict these distances are still at infancy. To advance these methods and develop other novel methods, we need a small and representative dataset packaged for fast development and testing. In this work, we introduce Protein Distance Net (PDNET), a dataset derived from the widely used DeepCov dataset and consists of 3456 representative protein chains for training and validation. It is packaged with all the scripts that were used to curate the dataset, generate the input features and distance maps, and scripts with deep learning models to train, validate and test. Deep learning models can also be trained and tested in a web browser using free platforms such as Google Colab. We discuss how this dataset can be used to predict contacts, distance intervals, and real-valued distances (in Å) by designing regression models. All scripts, training data, deep learning code for training, validation, and testing, and Python notebooks are available at https://github.com/ba-lab/pdnet/.

scholarly journals Improving deep learning-based protein distance prediction in CASP14

2021 ◽  
Author(s):  
Zhiye Guo ◽  
Tianqi Wu ◽  
Jian Liu ◽  
Jie Hou ◽  
Jianlin Cheng
Keyword(s):  
Deep Learning ◽  
Protein Structure ◽  
Protein Structure Prediction ◽  
Structure Prediction ◽  
Prediction Method ◽  
Learning Method ◽  
Sequence Alignments ◽  
Evolutionary Features ◽  
Protein Distance ◽  
Distance Prediction

AbstractAccurate 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. 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 ranked 6th among automated server predictors in classifying inter-residue distances into 10 distance intervals defined by CASP14 according to the F1 measure. 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.

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