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Cited by 193Machine Learning in BioinformaticsComputational Drug Discovery MethodsEnzyme Catalysis and Immobilization

The DOI matches its Crossref record; 71 of the 73 references it cites were found in a registry or an index.

A general model to predict small molecule substrates of enzymes based on machine and deep learning

Open access
Kroll, Alexander, Ranjan, Sahasra, Engqvist, Martin K. M., Lercher, Martin J.·2023·Nature Communications
DOI 10.1038/s41467-023-38347-2PMC PMC10185530
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Abstract

For most proteins annotated as enzymes, it is unknown which primary and/or secondary reactions they catalyze. Experimental characterizations of potential substrates are time-consuming and costly. Machine learning predictions could provide an efficient alternative, but are hampered by a lack of information regarding enzyme non-substrates, as available training data comprises mainly positive examples. Here, we present ESP, a general machine-learning model for the prediction of enzyme-substrate pairs with an accuracy of over 91% on independent and diverse test data. ESP can be applied successfully across widely different enzymes and a broad range of metabolites included in the training data, outperforming models designed for individual, well-studied enzyme families. ESP represents enzymes through a modified transformer model, and is trained on data augmented with randomly sampled small molecules assigned as non-substrates. By facilitating easy in silico testing of potential substrates, the ESP web server may support both basic and applied science.

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Crossref · 10.1038/s41467-023-38347-2

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Fig. 1 Model overview. Experimentally validated enzyme-substrate pairs and sampled negative enzyme-small metabolite pairs are numerically represented with task-specific enzyme and small molecule representations. Concatenated enzyme-small molecule representations are used to train a gradient-boosting model. After training, the fitted model can be used to predict promising candidate substrates for enzymes.
Fig. 1 Model overview. Experimentally validated enzyme-substrate pairs and sampled negative enzyme-small metabolite pairs are numerically represented with task-specific enzyme and small molecule representations. Concatenated enzyme-small molecule representations are used to train a gradient-boosting model. After training, the fitted model can be used to predict promising candidate substrates for enzymes.CC BY · PubMed Central
Fig. 2 A task-specific enzyme representation developed from the ESM-1b model. a ESM-1b model. Amino acids of a protein sequence are represented with numerical vectors and passed through a transformer network. Some amino acid representations are masked. All representations are iteratively updated 33 times, using information about neighboring and distant amino acids. The ESM-1b model is trained to predict the masked amino acids. ESM-1b vectors are calculated by taking the element-wise mean of all representations in the last layer. b Modified ESM-1b model. An additional representation for the whole enzyme is added to the amino acid representations. After updating all representations 33 times, the enzyme representation is concatenated with a small molecule representation. The network is trained to predict whether the small molecule is a substrate for the given enzyme. After training, the ESM-1bts vector is extracted as the enzyme representation before adding the small molecule representation.
Fig. 2 A task-specific enzyme representation developed from the ESM-1b model. a ESM-1b model. Amino acids of a protein sequence are represented with numerical vectors and passed through a transformer network. Some amino acid representations are masked. All representations are iteratively updated 33 times, using information about neighboring and distant amino acids. The ESM-1b model is trained to predict the masked amino acids. ESM-1b vectors are calculated by taking the element-wise mean of all representations in the last layer. b Modified ESM-1b model. An additional representation for the whole enzyme is added to the amino acid representations. After updating all representations 33 times, the enzyme representation is concatenated with a small molecule representation. The network is trained to predict whether the small molecule is a substrate for the given enzyme. After training, the ESM-1bts vector is extracted as the enzyme representation before adding the small molecule representation.CC BY · PubMed Central
Fig. 3 Optimized models provide accurate predictions of enzyme-substrate pairs. a Accuracies. Boxplots summarize the results of the CV with n = 5 folds on the training set with the best sets of hyperparameters. We used a 2 × interquartile range for the whiskers, the boxes extend from the lower to upper quartile values, and the red horizontal lines are displaying the median of the data points. Blue dots display the accuracies on the test set, using the optimized models trained on the whole training set. b ROC curves for the test set. The dotted line displays the ROC curve expected for a completely random model. Source data are provided as a Source Data file.
Fig. 3 Optimized models provide accurate predictions of enzyme-substrate pairs. a Accuracies. Boxplots summarize the results of the CV with n = 5 folds on the training set with the best sets of hyperparameters. We used a 2 × interquartile range for the whiskers, the boxes extend from the lower to upper quartile values, and the red horizontal lines are displaying the median of the data points. Blue dots display the accuracies on the test set, using the optimized models trained on the whole training set. b ROC curves for the test set. The dotted line displays the ROC curve expected for a completely random model. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 Accurate predictions even for enzymes with distinct sequence similarity compared to enzymes in the training data. We divided the test set into subsets with different levels of enzyme sequence identity compared to enzymes in the training set. a ESP accuracies, calculated separately for enzyme-small molecule pairs where the small molecule occurred in the training set and where it did not occur in the training set. b ESP ROC curves. The dotted line displays the ROC curve expected for a completely random model. Source data are provided as a Source Data file.
Fig. 4 Accurate predictions even for enzymes with distinct sequence similarity compared to enzymes in the training data. We divided the test set into subsets with different levels of enzyme sequence identity compared to enzymes in the training set. a ESP accuracies, calculated separately for enzyme-small molecule pairs where the small molecule occurred in the training set and where it did not occur in the training set. b ESP ROC curves. The dotted line displays the ROC curve expected for a completely random model. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 Model performance increases with training set size. Points show accuracies and ROC-AUC scores for the test set versus the fraction of the available training data used for training the gradient-boosting model. Source data are provided as a Source Data file.
Fig. 5 Model performance increases with training set size. Points show accuracies and ROC-AUC scores for the test set versus the fraction of the available training data used for training the gradient-boosting model. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 Prediction scores around 0.5 indicate model uncertainty. Stacked histogram bars display the prediction score distributions of true predictions (blue) and false predictions (red). The inset shows a blow-up of the interval [0.2, 0.8]. Source data are provided as a Source Data file.
Fig. 6 Prediction scores around 0.5 indicate model uncertainty. Stacked histogram bars display the prediction score distributions of true predictions (blue) and false predictions (red). The inset shows a blow-up of the interval [0.2, 0.8]. Source data are provided as a Source Data file.CC BY · PubMed Central

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Research works printed but not linked: 4

  1. Cooper, G. M., Hausman, R. E. & Hausman, R. E.The Cell: A Molecular Approach, vol. 4 (ASM press, Washington DC, 2007).
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Metadata

Authors
Kroll, A., Ranjan, S., Engqvist, M. K. M., & Lercher, M. J.
Affiliations
  • Heinrich Heine University Düsseldorf (DE)
  • Indian Institute of Technology Bombay (IN)
  • EnginZyme (Sweden) (SE)
Corresponding author
Lercher, Martin J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-05-15
Volume
14
Issue
1
Pages
2787-2787
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-38347-2
PMC
PMC10185530
OpenAlex
W4376601927
Cited by
193
References
73
Citations by year
2026: 65 · 2025: 64 · 2024: 51 · 2023: 13
FWCI
17.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Chalmers Research (Chalmers University of Technology) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Univ. Duesseldorf: Duesseldorfer Dokumenten- und Publikationsserver (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (CRC 1310 + 390686111)
  • Volkswagen Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
Keywords
enzyme catalysis, transformer models, deep learning, metabolites
MeSH terms
Machine Learning, Deep Learning, Catalysis, Proteins, Support Vector Machine

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