MAERM: Predicting Enzyme-Reaction Matching Relationships with a Mixed-Attention Model

Abstract Harnessing enzyme specificity requires a thorough understanding of enzyme promiscuity, which determines enzymes’ catalytic scope; however, measuring this scope still relies heavily on labor-intensive analytical approaches. While data-driven approaches have emerged to predict the catalytic scope of enzymes, these methods continue to face challenges such as restricted datasets and insufficient integration of enzyme structural information and reaction transformations. Here, we introduce MAERM, an innovative mixed-attention model designed to predict enzyme-reaction matching relationships. Built on our MAERM-DB, a dataset with broad coverage of validated and chemoenzymatic catalysis data, MAERM utilizes a local-global attention module to integrate multimodal enzyme information with fine-grained reaction representations, thereby predicting enzyme-reaction matching probabilities. Results show that MAERM consistently outperforms all baselines, with an average F1-score of 0.984. Notably, on challenging test samples with less than 40% sequence identity to the training set, MAERM outperforms the second-ranked model by 5.9% in F1-score. In addition, MAERM achieves the highest top-10 success rate of 51.7% on Enzyme-405 and the highest balanced accuracy of 0.697 on BioCat-547, further supporting its generalizability in enzyme screening and chemoenzymatic catalysis. Finally, MAERM can serve as an efficient scoring module. When integrated with ProteinMPNN, MAERM has successfully guided novel enzyme design for two carbonyl reduction reactions, resulting in enhanced catalytic potential for the native substrate and demonstrating broad compatibility. Overall, MAERM has the potential to reduce the experimental cost of measuring enzymes’ catalytic scope, facilitate enzyme design, and ultimately accelerate the design-build-test-learn cycle in enzyme engineering.