Inter-residue Distance Prediction Research Articles

SASA-Net: A Spatial-Aware Self-Attention Mechanism for Building Protein 3D Structure Directly From Inter- Residue Distances.

Protein functions are tightly related to the fine details of their 3D structures. To understand protein structures, computational prediction approaches are highly needed. Recently, protein structure prediction has achieved considerable progresses mainly due to the increased accuracy of inter-residue distance estimation and the application of deep learning techniques. Most of the distance-based ab initio prediction approaches adopt a two-step diagram: constructing a potential function based on the estimated inter-residue distances, and then build a 3D structure that minimizes the potential function. These approaches have proven very promising; however, they still suffer from several limitations, especially the inaccuracies incurred by the handcrafted potential function. Here, we present SASA-Net, a deep learning-based approach that directly learns protein 3D structure from the estimated inter-residue distances. Unlike the existing approach simply representing protein structures as coordinates of atoms, SASA-Net represents protein structures using pose of residues, i.e., the coordinate system of each individual residue in which all backbone atoms of this residue are fixed. The key element of SASA-Net is a spatial-aware self-attention mechanism, which is able to adjust a residue's pose according to all other residues' features and the estimated distances between residues. By iteratively applying the spatial-aware self-attention mechanism, SASA-Net continuously improves the structure and finally acquires a structure with high accuracy. Using the CATH35 proteins as representatives, we demonstrate that SASA-Net is able to accurately and efficiently build structures from the estimated inter-residue distances. The high accuracy and efficiency of SASA-Net enables an end-to-end neural network model for protein structure prediction through combining SASA-Net and an neural network for inter-residue distance prediction. Source code of SASA-Net is available at https://github.com/gongtiansu/SASA-Net/.

A stacked meta-ensemble for protein inter-residue distance prediction

Predicted inter-residue distances are a key behind recent success in high quality protein structure prediction (PSP). However, prediction of both short and long distance values together is challenging. Consequently, predicted short distances are mostly used by existing PSP methods. In this paper, we use a stacked meta-ensemble method to combine deep learning models trained for different ranges of real-valued distances. On five benchmark sets of proteins, our proposed inter-residue distance prediction method improves mean Local Distance Different Test (LDDT) scores at least by 5% over existing such methods. Moreover, using a real-valued distance based conformational search algorithm, we also show that predicted long distances help obtain significantly better protein conformations than when only predicted short distances are used. Our method is named meta-ensemble for distance prediction (MDP) and its program is available from https://gitlab.com/mahnewton/mdp.

Inter-Residue Distance Prediction From Duet Deep Learning Models.

Residue distance prediction from the sequence is critical for many biological applications such as protein structure reconstruction, protein–protein interaction prediction, and protein design. However, prediction of fine-grained distances between residues with long sequence separations still remains challenging. In this study, we propose DuetDis, a method based on duet feature sets and deep residual network with squeeze-and-excitation (SE), for protein inter-residue distance prediction. DuetDis embraces the ability to learn and fuse features directly or indirectly extracted from the whole-genome/metagenomic databases and, therefore, minimize the information loss through ensembling models trained on different feature sets. We evaluate DuetDis and 11 widely used peer methods on a large-scale test set (610 proteins chains). The experimental results suggest that 1) prediction results from different feature sets show obvious differences; 2) ensembling different feature sets can improve the prediction performance; 3) high-quality multiple sequence alignment (MSA) used for both training and testing can greatly improve the prediction performance; and 4) DuetDis is more accurate than peer methods for the overall prediction, more reliable in terms of model prediction score, and more robust against shallow multiple sequence alignment (MSA).

Enhancing protein inter-residue real distance prediction by scrutinising deep learning models

Protein structure prediction (PSP) has achieved significant progress lately via prediction of inter-residue distances using deep learning models and exploitation of the predictions during conformational search. In this context, prediction of large inter-residue distances and also prediction of distances between residues separated largely in the protein sequence remain challenging. To deal with these challenges, state-of-the-art inter-residue distance prediction algorithms have used large sets of coevolutionary and non-coevolutionary features. In this paper, we argue that the more the types of features used, the more the kinds of noises introduced and then the deep learning model has to overcome the noises to improve the accuracy of the predictions. Also, multiple features capturing similar underlying characteristics might not necessarily have significantly better cumulative effect. So we scrutinise the feature space to reduce the types of features to be used, but at the same time, we strive to improve the prediction accuracy. Consequently, for inter-residue real distance prediction, in this paper, we propose a deep learning model named scrutinised distance predictor (SDP), which uses only 2 coevolutionary and 3 non-coevolutionary features. On several sets of benchmark proteins, our proposed SDP method improves mean Local Distance Different Test (LDDT) scores at least by 10% over existing state-of-the-art methods. The SDP program along with its data is available from the website https://gitlab.com/mahnewton/sdp.

Toward the assessment of predicted inter-residue distance.

Significant progress has been achieved in distance-based protein folding, due to improved prediction of inter-residue distance by deep learning. Many efforts are thus made to improve distance prediction in recent years. However, it remains unknown what is the best way of objectively assessing the accuracy of predicted distance. A total of 19 metrics were proposed to measure the accuracy of predicted distance. These metrics were discussed and compared quantitatively on three benchmark datasets, with distance and structure models predicted by the trRosetta pipeline. The experiments show that a few metrics, such as distance precision, have a high correlation with the model accuracy measure TM-score (Pearson's correlation coefficient >0.7). In addition, the metrics are applied to rank the distance prediction groups in CASP14. The ranking by our metrics coincides largely with the official version. These data suggest that the proposed metrics are effective for measuring distance prediction. We anticipate that this study paves the way for objectively monitoring the progress of inter-residue distance prediction. A web server and a standalone package are provided to implement the proposed metrics. http://yanglab.nankai.edu.cn/APD. Supplementary data are available at Bioinformatics online.

Protein model accuracy estimation empowered by deep learning and inter-residue distance prediction in CASP14

The inter-residue contact prediction and deep learning showed the promise to improve the estimation of protein model accuracy (EMA) in the 13th Critical Assessment of Protein Structure Prediction (CASP13). To further leverage the improved inter-residue distance predictions to enhance EMA, during the 2020 CASP14 experiment, we integrated several new inter-residue distance features with the existing model quality assessment features in several deep learning methods to predict the quality of protein structural models. According to the evaluation of performance in selecting the best model from the models of CASP14 targets, our three multi-model predictors of estimating model accuracy (MULTICOM-CONSTRUCT, MULTICOM-AI, and MULTICOM-CLUSTER) achieve the averaged loss of 0.073, 0.079, and 0.081, respectively, in terms of the global distance test score (GDT-TS). The three methods are ranked first, second, and third out of all 68 CASP14 predictors. MULTICOM-DEEP, the single-model predictor of estimating model accuracy (EMA), is ranked within top 10 among all the single-model EMA methods according to GDT-TS score loss. The results demonstrate that inter-residue distance features are valuable inputs for deep learning to predict the quality of protein structural models. However, larger training datasets and better ways of leveraging inter-residue distance information are needed to fully explore its potentials.

Study of real-valued distance prediction for protein structure prediction with deep learning.

Inter-residue distance prediction by convolutional residual neural network (deep ResNet) 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 fold a protein by the predicted mean and deviation. Our findings include: (i) 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%); (ii) 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; (iii) our method greatly outperforms a very new real-valued prediction method DeepDist in both contact prediction and 3D structure modeling and (iv) 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. https://github.com/j3xugit/RaptorX-3DModeling. Supplementary data are available at Bioinformatics online.

Analyzing effect of quadruple multiple sequence alignments on deep learning based protein inter-residue distance prediction

Protein 3D structure prediction has advanced significantly in recent years due to improving contact prediction accuracy. This improvement has been largely due to deep learning approaches that predict inter-residue contacts and, more recently, distances using multiple sequence alignments (MSAs). In this work we present AttentiveDist, a novel approach that uses different MSAs generated with different E-values in a single model to increase the co-evolutionary information provided to the model. To determine the importance of each MSA’s feature at the inter-residue level, we added an attention layer to the deep neural network. We show that combining four MSAs of different E-value cutoffs improved the model prediction performance as compared to single E-value MSA features. A further improvement was observed when an attention layer was used and even more when additional prediction tasks of bond angle predictions were added. The improvement of distance predictions were successfully transferred to achieve better protein tertiary structure modeling.

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

BackgroundDriven 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.ResultsTo 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 Å2 when filtering out the predicted distance ≥ 16 Å, which is lower than 1.003 Å2 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 results in the CASP13 experiment.ConclusionsDeepDist 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.

A Review of Protein Inter-residue Distance Prediction

Proteins are large molecules consisting of a linear sequence of amino acids. Protein performs biological functions with specific 3D structures. The main factors that drive proteins to form these structures are constraint between residues. These constraints usually lead to important inter-residue relationships, including short-range inter-residue contacts and long-range interresidue distances. Thus, a highly accurate prediction of inter-residue contact and distance information is of great significance for protein tertiary structure computations. Some methods have been proposed for inter-residue contact prediction, most of which focus on contact map prediction and some reviews have summarized the progresses. However, inter-residue distance prediction is found to provide better guidance for protein structure prediction than contact map prediction in recent years. The methods for inter-residue distance prediction can be roughly divided into two types according to the consideration of distance value: one is based on multi-classification with discrete value and the other is based on regression with continuous value. Here, we summarize these algorithms and show that they have obtained good results. Compared to contact map prediction, distance map prediction is in its infancy. There is a lot to do in the future including improving distance map prediction precision and incorporating them into residue-residue distanceguided ab initio protein folding.

New Labeling Methods for Deep Learning Real-Valued Inter-Residue Distance Prediction.

Much of the recent success in protein structure prediction has been a result of accurate protein contact prediction-a binary classification problem. Dozens of methods, built from various types of machine learning and deep learning algorithms, have been published over the last two decades for predicting contacts. Recently, many groups, including Google DeepMind, have demonstrated that reformulating the problem as a multi-class classification problem is a more promising direction to pursue. As an alternative approach, we recently proposed real-valued distance predictions, formulating the problem as a regression problem. The nuances of protein 3D structures make this formulation appropriate, allowing predictions to reflect inter-residue distances in nature. Despite these promises, the accurate prediction of real-valued distances remains relatively unexplored; possibly due to classification being better suited to machine and deep learning algorithms. Can regression methods be designed to predict real-valued distances as precise as binary contacts? To investigate this, we propose multiple novel methods of input label engineering, which is different from feature engineering, with the goal of optimizing the distribution of distances to cater to the loss function of the deep-learning model. Since an important utility of predicted contacts or distances is to build three-dimensional models, we also tested if predicted distances can reconstruct more accurate models than contacts. Our results demonstrate, for the first time, that deep learning methods for real-valued protein distance prediction can deliver distances as precise as binary classification methods. When using an optimal distance transformation function on the standard PSICOV dataset consisting of 150 representative proteins, the precision of 'top-all' long-range contacts improves from 60.9% to 61.4% when predicting real-valued distances instead of contacts. When building three-dimensional models we observed an average TM-score increase from 0.61 to 0.72, highlighting the advantage of predicting real-valued distances.

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

As deep learning algorithms drive the progress in protein structure prediction, a lot remains to be studied at this merging superhighway 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 predicting accurate models. However, deep learning methods that predict these distances are still in the early stages of their development. To advance these methods and develop other novel methods, a need exists for a small and representative dataset packaged for faster development and testing. In this work, we introduce protein distance net (PDNET), a framework that consists of one such representative dataset along with the scripts for training and testing deep learning methods. The framework also includes all the scripts that were used to curate the dataset, and generate the input features and distance maps. Deep learning models can also be trained and tested in a web browser using free platforms such as Google Colab. We discuss how PDNET can be used to predict contacts, distance intervals, and real-valued distances.