EZSolver: Template-free prediction of polar enzymatic mechanisms via bidirectional flow matching and search
Predicting enzymatic reaction mechanisms is critical for understanding enzyme function and for designing and discovering new enzymes. Current computational predictors rely on deterministic, rule-based dictionaries, which perform well on in-distribution tasks but fail to generalize to out-of-distribution (OOD) chemistry. To address this limitation, we present EZSolver, a template-free, generative framework for polar enzymatic mechanism prediction. Powered by a flow matching predictor (EZFlow) and navigated by an evaluator-guided bidirectional beam search, EZSolver learns the chemistry of electron redistribution instead of memorizing rigid templates. Evaluated across diverse enzyme classes, EZSolver achieves a 60.0% accuracy and an 84.6% chemical plausibility rate for full mechanism prediction of unseen polar enzymatic reactions. While rule-based models collapse without predefined templates, EZSolver successfully extrapolates chemical knowledge to infer uncatalogued pathways, as demonstrated during rigorous OOD benchmarking. By illuminating enzymatic chemical mechanisms, EZSolver helps pave the way for automated prediction of enzyme function and discovery and design of novel biocatalysts for sustainable chemistry. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/737313v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1b0ad92org.highwire.dtl.DTLVardef@535a71org.highwire.dtl.DTLVardef@56e846org.highwire.dtl.DTLVardef@1ab76ec_HPS_FORMAT_FIGEXP M_FIG C_FIG