TIGER: Text-Informed Generalized Enzyme-Reaction Retrieval

Enzyme substrate interaction (ESI) prediction is a fundamental computational task for biocatalyst discovery and reaction screening in large biochemical spaces. In practical settings, ESI prediction is challenged by sparse positive supervision and low-homology distribution shift, where test enzymes share limited sequence identity with those observed during training. To address these challenges, we propose RAMMESI, a retrieval-augmented multimodal framework for robust ESI prediction. RAMMESI learns explicit pairwise enzyme-substrate representations through directional cross-modal interaction modeling and adaptive fusion. To enhance robustness, RAMMESI retrieves neighboring enzymes at inference time, recombines them with the query substrate, and aggregates the resulting pairwise predictions as contextual evidence. To improve learning under sparse positive supervision, we further adopt an imbalance-aware weighted-BCE objective. Experiments on two ESI benchmarks under sequence-identity-aware splits demonstrate that RAMMESI achieves consistently strong performance, with particular advantages in more challenging low-identity regimes. In addition, the retrieval module improves multiple ESI backbones in a plug-and-play manner, suggesting that retrieval provides a general mechanism for improving robustness under homology shift.

Enzyme function prediction is a hierarchical, knowledge-intensive form of protein function classification. Existing benchmarks expose an anomaly: general LLMs often get the coarse first level right, yet once asked for a complete EC number their accuracy at levels two through four drops to almost zero, while specialized models and tools stay usable. We propose EC-Reason-Bench, a training-free, diagnostic evaluation protocol built to answer two questions: why general LLMs score close to nothing on EC number prediction, and how much of that loss can be recovered without updating a single weight. We break enzyme classification ability into four orthogonal levers that can each be measured on their own: output structure, external knowledge, reasoning structure, and reasoning robustness. We test each lever with an inference-time method against a shared zero-shot baseline reproducing previously reported near-zero performance. Experiments with several strong reasoning LLMs yield four main findings. First, external knowledge is decisive and must precede reasoning: uniformly low closed-book performance rises sharply with open-book access, narrowing model gaps. Second, in closed-book settings, whether cascading and chain-of-thought help or hurt depends on a model's tendency to abstain. Third, once evidence is available the aggregate score of the best LLM setting is indistinguishable from simply voting the EC numbers of the nearest retrieved neighbors; that tie is an artifact of averaging, and it hides a large gain on adversarial evidence set against an equally large loss on multi-functional enzymes. Reasoning over evidence therefore acts as an arbiter of conflicting neighbors rather than as a source of knowledge, and no single-number leaderboard can see it. Fourth, accuracy obeys a law of homology availability.

Computational enzyme design requires generating proteins that scaffold catalytic residues and ligands, a task that demands both geometric accuracy and structural diversity from the underlying generative model. Current all-atom generators inherit expensive architectures from structure prediction, leading to high training costs and limited sample diversity. We argue that much of this complexity is unnecessary for generators, which condition on sparse geometric constraints rather than rich co-evolutionary signals. Emyx is a 140M-parameter conditional flow matching model that concentrates capacity within standard transformer blocks, replacing heavy embedding stacks with lightweight conditional representations and sparse connectivity. We additionally derive an exact reparametrisation of the flow matching interpolant into the EDM noise-level framework, bridging flow matching training efficiency with state-of-the-art sampling methods designed for diffusion models without retraining. Despite being the smallest model, Emyx outperforms both Proteína-Complexa and RFdiffusion3 against the AME enzyme design benchmark across success rate under strict evaluation requiring both global fold recovery and catalytic geometry accuracy, structural novelty, scaffold diversity, and geometric validity, while training in just $682$ GPU-hours, roughly $4\times$ less than RFdiffusion3.