TopEC: prediction of Enzyme Commission classes by 3D graph neural networks and localized 3D protein descriptor

Karel Weg, Erinc Merdivan, Marie Piraud and Holger Gohlke ()
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Karel Weg: Forschungszentrum Jülich GmbH
Erinc Merdivan: Helmholtz AI Central Unit, Ingolstädter Landstraße 1
Marie Piraud: Helmholtz AI Central Unit, Ingolstädter Landstraße 1
Holger Gohlke: Forschungszentrum Jülich GmbH

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Tools available for inferring enzyme function from general sequence, fold, or evolutionary information are generally successful. However, they can lead to misclassification if a deviation in local structural features influences the function. Here, we present TopEC, a 3D graph neural network based on a localized 3D descriptor to learn chemical reactions of enzymes from enzyme structures and predict Enzyme Commission (EC) classes. Using message-passing frameworks, we include distance and angle information to significantly improve the predictive performance for EC classification (F-score: 0.72) compared to regular 2D graph neural networks. We trained networks without fold bias that can classify enzyme structures for a vast functional space (>800 ECs). Our model is robust to uncertainties in binding site locations and similar functions in distinct binding sites. We observe that TopEC networks learn from an interplay between biochemical features and local shape-dependent features. TopEC is available as a repository on GitHub: https://github.com/IBG4-CBCLab/TopEC and https://doi.org/10.25838/d5p-66 .

Date: 2025
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DOI: 10.1038/s41467-025-57324-5

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