KineCouple: Substrate-conditioned residual readout for enzyme kinetic prediction

Chun Kang, Yunbo Zhang, Fanhu Zeng, Jian Liu, Siwei Deng +1

Accurate prediction of enzyme kinetic parameters can support enzyme engineering and metabolic modeling by complementing experimental characterization. Existing prediction methods often pool residue-level protein features before combining them with substrate features. Such substrate-independent pooling cannot adapt residue weighting to the substrate during aggregation, potentially diluting information relevant to a specific enzyme-substrate pair. Since the contributions of individual residues to catalysis can depend on the substrate, substrate-conditioned aggregation offers a way to emphasize residue features relevant to the prediction. We introduce KineCouple, which uses substrate queries and residue-level keys and values in cross-attention, allowing the substrate to guide residue selection before aggregation. The model preserves the global protein representation and adds a gated correction defined as the difference between the conditioned readout and a uniform readout. ProtT5 and MolT5 remain frozen, and separate models predict kcat and Km on a logarithmic scale. In pooled out-of-fold predictions on the CataPro benchmarks, KineCouple reduces kcat RMSE from 1.333 to 1.330 and…