# Interleaved Tool-Call Reasoning for Protein Function Understanding

arXiv: https://arxiv.org/abs/2601.03604 · HTML: https://mlsanity.com/paper/2601.03604/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 18 of its 28 references that are in the map.
- First posted on arXiv 7 Jan 2026.

## Placed in

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

## Builds on (most cited first, 18 of 18)

- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Qwen3 Technical Report](https://mlsanity.com/paper/2505.09388/) (2025)
- [ReAct: Synergizing Reasoning and Acting in Language Models](https://mlsanity.com/paper/2210.03629/) (2022)
- [DeepSeek-R1: Incentivizing Reasoning Capability in LLMs via Reinforcement Learning](https://mlsanity.com/paper/2501.12948/) (2025)
- [Self-Consistency Improves Chain of Thought Reasoning in Language Models](https://mlsanity.com/paper/2203.11171/) (2022)
- [Scaling LLM Test-Time Compute Optimally can be More Effective than Scaling Model Parameters](https://mlsanity.com/paper/2408.03314/) (2024)
- [Search-R1: Training LLMs to Reason and Leverage Search Engines with Reinforcement Learning](https://mlsanity.com/paper/2503.09516/) (2025)
- [Qwen2.5-Coder Technical Report](https://mlsanity.com/paper/2409.12186/) (2024)
- [Program of Thoughts Prompting: Disentangling Computation from Reasoning for Numerical Reasoning Tasks](https://mlsanity.com/paper/2211.12588/) (2022)
- [Does Reinforcement Learning Really Incentivize Reasoning Capacity in LLMs Beyond the Base Model?](https://mlsanity.com/paper/2504.13837/) (2025)
- [Kimi K2: Open Agentic Intelligence](https://mlsanity.com/paper/2507.20534/) (2025)
- [ReTool: Reinforcement Learning for Strategic Tool Use in LLMs](https://mlsanity.com/paper/2504.11536/) (2025)
- [R1-Searcher: Incentivizing the Search Capability in LLMs via Reinforcement Learning](https://mlsanity.com/paper/2503.05592/) (2025)
- [ToRL: Scaling Tool-Integrated RL](https://mlsanity.com/paper/2503.23383/) (2025)
- [Mol-Instructions: A Large-Scale Biomolecular Instruction Dataset for Large Language Models](https://mlsanity.com/paper/2306.08018/) (2023)
- [ProtT3: Protein-to-Text Generation for Text-based Protein Understanding](https://mlsanity.com/paper/2405.12564/) (2024)
- [EvoLlama: Enhancing LLMs' Understanding of Proteins via Multimodal Structure and Sequence Representations](https://mlsanity.com/paper/2412.11618/) (2024)
- [Prot2Text-V2: Protein Function Prediction with Multimodal Contrastive Alignment](https://mlsanity.com/paper/2505.11194/) (2025)

## Built on by (most cited first, 1 of 1)

- [BioMatrix: Towards a Comprehensive Biological Foundation Model Spanning the Modality Matrix of Sequences, Structures, and Language](https://mlsanity.com/paper/2606.22138/) (2026)

## Abstract (arXiv)

Recent advances in large language models (LLMs) have highlighted the effectiveness of chain-of-thought reasoning in symbolic domains such as mathematics and programming. However, our study shows that directly transferring such text-based reasoning paradigms to protein function understanding is ineffective: reinforcement learning mainly amplifies superficial keyword patterns while failing to introduce new biological knowledge, resulting in limited generalization. We argue that protein function prediction is a knowledge-intensive scientific task that fundamentally relies on external biological priors and computational tools rather than purely internal reasoning. To address this gap, we propose PFUA, a tool-augmented protein reasoning agent that unifies problem decomposition, tool invocation, and grounded answer generation. Instead of relying on long unconstrained reasoning traces, PFUA integrates domain-specific tools to produce verifiable intermediate evidence. Experiments on four benchmarks demonstrate that PFUA consistently outperforms text-only reasoning models with an average performance improvement of 103%.