Dataset Information

Using deep-learning predictions of inter-residue distances for model validation.

ABSTRACT: Determination of protein structures typically entails building a model that satisfies the collected experimental observations and its deposition in the Protein Data Bank. Experimental limitations can lead to unavoidable uncertainties during the process of model building, which result in the introduction of errors into the deposited model. Many metrics are available for model validation, but most are limited to consideration of the physico-chemical aspects of the model or its match to the experimental data. The latest advances in the field of deep learning have enabled the increasingly accurate prediction of inter-residue distances, an advance which has played a pivotal role in the recent improvements observed in the field of protein ab initio modelling. Here, new validation methods are presented based on the use of these precise inter-residue distance predictions, which are compared with the distances observed in the protein model. Sequence-register errors are particularly clearly detected and the register shifts required for their correction can be reliably determined. The method is available in the ConKit package (https://www.conkit.org).

SUBMITTER: Sanchez Rodriguez F

PROVIDER: S-EPMC9716559 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Using deep-learning predictions of inter-residue distances for model validation.

Sánchez Rodríguez Filomeno F Chojnowski Grzegorz G Keegan Ronan M RM Rigden Daniel J DJ

Acta crystallographica. Section D, Structural biology 20221125 Pt 12

Determination of protein structures typically entails building a model that satisfies the collected experimental observations and its deposition in the Protein Data Bank. Experimental limitations can lead to unavoidable uncertainties during the process of model building, which result in the introduction of errors into the deposited model. Many metrics are available for model validation, but most are limited to consideration of the physico-chemical aspects of the model or its match to the experim ...[more]

PMID: 36458613

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Project description:BackgroundProtein inter-residue contact maps provide a translation and rotation invariant topological representation of a protein. They can be used as an intermediary step in protein structure predictions. However, the prediction of contact maps represents an unbalanced problem as far fewer examples of contacts than non-contacts exist in a protein structure.In this study we explore the possibility of completely eliminating the unbalanced nature of the contact map prediction problem by predicting real-value distances between residues. Predicting full inter-residue distance maps and applying them in protein structure predictions has been relatively unexplored in the past.ResultsWe initially demonstrate that the use of native-like distance maps is able to reproduce 3D structures almost identical to the targets, giving an average RMSD of 0.5Å. In addition, the corrupted physical maps with an introduced random error of ±6Å are able to reconstruct the targets within an average RMSD of 2Å.After demonstrating the reconstruction potential of distance maps, we develop two classes of predictors using two-dimensional recursive neural networks: an ab initio predictor that relies only on the protein sequence and evolutionary information, and a template-based predictor in which additional structural homology information is provided. We find that the ab initio predictor is able to reproduce distances with an RMSD of 6Å, regardless of the evolutionary content provided. Furthermore, we show that the template-based predictor exploits both sequence and structure information even in cases of dubious homology and outperforms the best template hit with a clear margin of up to 3.7Å.Lastly, we demonstrate the ability of the two predictors to reconstruct the CASP9 targets shorter than 200 residues producing the results similar to the state of the machine learning art approach implemented in the Distill server.ConclusionsThe methodology presented here, if complemented by more complex reconstruction protocols, can represent a possible path to improve machine learning algorithms for 3D protein structure prediction. Moreover, it can be used as an intermediary step in protein structure predictions either on its own or complemented by NMR restraints.

Project description:MotivationDeep learning has become the dominant technology for protein contact prediction. However, the factors that affect the performance of deep learning in contact prediction have not been systematically investigated.ResultsWe analyzed the results of our three deep learning-based contact prediction methods (MULTICOM-CLUSTER, MULTICOM-CONSTRUCT and MULTICOM-NOVEL) in the CASP13 experiment and identified several key factors [i.e. deep learning technique, multiple sequence alignment (MSA), distance distribution prediction and domain-based contact integration] that influenced the contact prediction accuracy. We compared our convolutional neural network (CNN)-based contact prediction methods with three coevolution-based methods on 75 CASP13 targets consisting of 108 domains. We demonstrated that the CNN-based multi-distance approach was able to leverage global coevolutionary coupling patterns comprised of multiple correlated contacts for more accurate contact prediction than the local coevolution-based methods, leading to a substantial increase of precision by 19.2 percentage points. We also tested different alignment methods and domain-based contact prediction with the deep learning contact predictors. The comparison of the three methods showed deeper sequence alignments and the integration of domain-based contact prediction with the full-length contact prediction improved the performance of contact prediction. Moreover, we demonstrated that the domain-based contact prediction based on a novel ab initio approach of parsing domains from MSAs alone without using known protein structures was a simple, fast approach to improve contact prediction. Finally, we showed that predicting the distribution of inter-residue distances in multiple distance intervals could capture more structural information and improve binary contact prediction.Availability and implementationhttps://github.com/multicom-toolbox/DNCON2/.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:Study objectivesDevelopment of inter-database generalizable sleep staging algorithms represents a challenge due to increased data variability across different datasets. Sharing data between different centers is also a problem due to potential restrictions due to patient privacy protection. In this work, we describe a new deep learning approach for automatic sleep staging, and address its generalization capabilities on a wide range of public sleep staging databases. We also examine the suitability of a novel approach that uses an ensemble of individual local models and evaluate its impact on the resulting inter-database generalization performance.MethodsA general deep learning network architecture for automatic sleep staging is presented. Different preprocessing and architectural variant options are tested. The resulting prediction capabilities are evaluated and compared on a heterogeneous collection of six public sleep staging datasets. Validation is carried out in the context of independent local and external dataset generalization scenarios.ResultsBest results were achieved using the CNN_LSTM_5 neural network variant. Average prediction capabilities on independent local testing sets achieved 0.80 kappa score. When individual local models predict data from external datasets, average kappa score decreases to 0.54. Using the proposed ensemble-based approach, average kappa performance on the external dataset prediction scenario increases to 0.62. To our knowledge this is the largest study by the number of datasets so far on validating the generalization capabilities of an automatic sleep staging algorithm using external databases.ConclusionsValidation results show good general performance of our method, as compared with the expected levels of human agreement, as well as to state-of-the-art automatic sleep staging methods. The proposed ensemble-based approach enables flexible and scalable design, allowing dynamic integration of local models into the final ensemble, preserving data locality, and increasing generalization capabilities of the resulting system at the same time.

Dataset Information

Using deep-learning predictions of inter-residue distances for model validation.

Publications

Using deep-learning predictions of inter-residue distances for model validation.

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