# Knowledge before Reasoning: EC-Reason-Bench, a Training-Free Diagnostic Benchmark for LLM Enzyme Classification

arXiv: https://arxiv.org/abs/2607.26397 · HTML: https://mlsanity.com/paper/2607.26397/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 7 of its 55 references that are in the map.
- First posted on arXiv 29 Jul 2026.

## Placed in

- LLM reasoning / [Clinical and biomedical applications](https://mlsanity.com/lr/clinical-and-biomedical-applications/)

## Builds on (most cited first, 7 of 7)

- [ReAct: Synergizing Reasoning and Acting in Language Models](https://mlsanity.com/paper/2210.03629/) (2022)
- [Self-Consistency Improves Chain of Thought Reasoning in Language Models](https://mlsanity.com/paper/2203.11171/) (2022)
- [GPT-4o System Card](https://mlsanity.com/paper/2410.21276/) (2024)
- [Least-to-Most Prompting Enables Complex Reasoning in Large Language Models](https://mlsanity.com/paper/2205.10625/) (2022)
- [Protriever: End-to-End Differentiable Protein Homology Search for Fitness Prediction](https://mlsanity.com/paper/2506.08954/) (2025)
- [PQA: Zero-shot Protein Question Answering for Free-form Scientific Enquiry with Large Language Models](https://mlsanity.com/paper/2402.13653/) (2024)
- [Knowledge-Augmented Long-CoT Generation for Complex Biomolecular Reasoning](https://mlsanity.com/paper/2511.08024/) (2025)

## Abstract (arXiv)

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.