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Background: The accurate computational prediction of B cell epitopes can vastly reduce the cost and time required for identifying potential epitope candidates for the design of vaccines and immunodiagnostics. However, current computational tools for B cell epitope prediction perform poorly and are not fit-for-purpose, and there remains enormous room for improvement and the need for superior prediction strategies. Results: Here we propose a novel approach that improves B cell epitope prediction by encoding epitopes as binary positional permutation vectors that represent the position and structural properties of the amino acids within a protein antigen sequence that interact with an antibody. This approach supersedes the traditional method of defining epitopes as scores per amino acid on a protein sequence, where each score reflects each amino acids predicted probability of partaking in a B cell epitope antibody interaction. In addition to defining epitopes as binary positional permutation vectors, the approach also uses the 3D macrostructure features of the unbound protein structures, and in turn uses these features to train another deep learning model on the corresponding antibody-bound protein 3D structures. This enables the algorithm to learn the key structural and physiochemical features of the unbound protein and embedded epitope that initiate the antibody binding process helping to eliminate “induced fit” biases in the training data. We demonstrate that the strategy predicts B cell epitopes with improved accuracy compared to the existing tools. Additionally, we show that this approach reliably identifies the majority of experimentally verified epitopes on the spike protein of SARS-CoV-2 not seen by the model during training and generalizes in a very robust manner on dissimilar data not seen by the model during training. Conclusions: With the approach described herein, a primary protein sequence and a query positional permutation vector encoding a putative epitope is sufficient to predict B cell epitopes in a reliable manner, potentially advancing the use of computational prediction of B cell epitopes in biomedical research applications.

Accurate computational identification of B-cell epitopes is crucial for the development of vaccines, therapies, and diagnostic tools. However, current structure-based prediction methods face limitations due to the dependency on experimentally solved structures. Here, we introduce DiscoTope-3.0, a markedly improved B-cell epitope prediction tool that innovatively employs inverse folding structure representations and a positive-unlabelled learning strategy, and is adapted for both solved and predicted structures. Our tool demonstrates a considerable improvement in performance over existing methods, accurately predicting linear and conformational epitopes across multiple independent datasets. Most notably, DiscoTope-3.0 maintains high predictive performance across solved, relaxed and predicted structures, alleviating the need for experimental structures and extending the general applicability of accurate B-cell epitope prediction by 3 orders of magnitude. DiscoTope-3.0 is made widely accessible on two web servers, processing over 100 structures per submission, and as a downloadable package. In addition, the servers interface with RCSB and AlphaFoldDB, facilitating large-scale prediction across over 200 million cataloged proteins. DiscoTope-3.0 is available at: https://services.healthtech.dtu.dk/service.php?DiscoTope-3.0. [ABSTRACT FROM AUTHOR]

Accurate computational identification of B-cell epitopes is crucial for the development of vaccines, therapies, and diagnostic tools. However, current structure-based prediction methods face limitations due to the dependency on experimentally solved structures. Here, we introduce DiscoTope-3.0, a markedly improved B-cell epitope prediction tool that innovatively employs inverse folding structure representations and a positive-unlabelled learning strategy, and is adapted for both solved and predicted structures. Our tool demonstrates a considerable improvement in performance over existing methods, accurately predicting linear and conformational epitopes across multiple independent datasets. Most notably, DiscoTope-3.0 maintains high predictive performance across solved, relaxed and predicted structures, alleviating the need for experimental structures and extending the general applicability of accurate B-cell epitope prediction by 3 orders of magnitude. DiscoTope-3.0 is made widely accessible on two web servers, processing over 100 structures per submission, and as a downloadable package. In addition, the servers interface with RCSB and AlphaFoldDB, facilitating large-scale prediction across over 200 million cataloged proteins. DiscoTope-3.0 is available at: https://services.healthtech.dtu.dk/service.php?DiscoTope-3.0.

Background: The accurate computational prediction of B cell epitopes can vastly reduce the cost and time required for identifying potential epitope candidates for the design of vaccines and immunodiagnostics. However, current computational tools for B cell epitope prediction perform poorly and are not fit-for-purpose, and there remains enormous room for improvement and the need for superior prediction strategies., Results: Here we propose a novel approach that improves B cell epitope prediction by encoding epitopes as binary positional permutation vectors that represent the position and structural properties of the amino acids within a protein antigen sequence that interact with an antibody. This approach supersedes the traditional method of defining epitopes as scores per amino acid on a protein sequence, where each score reflects each amino acids predicted probability of partaking in a B cell epitope antibody interaction. In addition to defining epitopes as binary positional permutation vectors, the approach also uses the 3D macrostructure features of the unbound protein structures, and in turn uses these features to train another deep learning model on the corresponding antibody-bound protein 3D structures. This enables the algorithm to learn the key structural and physiochemical features of the unbound protein and embedded epitope that initiate the antibody binding process helping to eliminate "induced fit" biases in the training data. We demonstrate that the strategy predicts B cell epitopes with improved accuracy compared to the existing tools. Additionally, we show that this approach reliably identifies the majority of experimentally verified epitopes on the spike protein of SARS-CoV-2 not seen by the model during training and generalizes in a very robust manner on dissimilar data not seen by the model during training., Conclusions: With the approach described herein, a primary protein sequence and a query positional permutation vector encoding a putative epitope is sufficient to predict B cell epitopes in a reliable manner, potentially advancing the use of computational prediction of B cell epitopes in biomedical research applications., Competing Interests: All authors are employees at the company NEC OncoImmunity AS., (© 2024 The Authors.)