# Knowledge-Augmented Long-CoT Generation for Complex Biomolecular Reasoning

arXiv: https://arxiv.org/abs/2511.08024 · HTML: https://mlsanity.com/paper/2511.08024/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Placed in Clinical and biomedical applications, one of 17 directions in LLM reasoning.
- Builds on 52 of its 61 references that are in the map.
- First posted on arXiv 11 Nov 2025.

## Placed in

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

## Builds on (most cited first, 30 of 52)

- [Chain-of-Thought Prompting Elicits Reasoning in Large Language Models](https://mlsanity.com/paper/2201.11903/) (2022)
- [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)
- [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)
- [GPT-4o System Card](https://mlsanity.com/paper/2410.21276/) (2024)
- [Large Language Models are Zero-Shot Reasoners](https://mlsanity.com/paper/2205.11916/) (2022)
- [Gemini 2.5: Pushing the Frontier with Advanced Reasoning, Multimodality, Long Context, and Next Generation Agentic Capabilities](https://mlsanity.com/paper/2507.06261/) (2025)
- [Learn to Explain: Multimodal Reasoning via Thought Chains for Science Question Answering](https://mlsanity.com/paper/2209.09513/) (2022)
- [A Survey on Hallucination in Large Language Models: Principles, Taxonomy, Challenges, and Open Questions](https://mlsanity.com/paper/2311.05232/) (2023)
- [Least-to-Most Prompting Enables Complex Reasoning in Large Language Models](https://mlsanity.com/paper/2205.10625/) (2022)
- [What Disease does this Patient Have? A Large-scale Open Domain Question Answering Dataset from Medical Exams](https://mlsanity.com/paper/2009.13081/) (2020)
- [s1: Simple test-time scaling](https://mlsanity.com/paper/2501.19393/) (2025)
- [PubMedQA: A Dataset for Biomedical Research Question Answering](https://mlsanity.com/paper/1909.06146/) (2019)
- [MetaMath: Bootstrap Your Own Mathematical Questions for Large Language Models](https://mlsanity.com/paper/2309.12284/) (2023)
- [ChemCrow: Augmenting large-language models with chemistry tools](https://mlsanity.com/paper/2304.05376/) (2023)
- [Complexity-Based Prompting for Multi-Step Reasoning](https://mlsanity.com/paper/2210.00720/) (2022)
- [Large Language Models Are Reasoning Teachers](https://mlsanity.com/paper/2212.10071/) (2022)
- [Teaching Small Language Models to Reason](https://mlsanity.com/paper/2212.08410/) (2022)
- [HuatuoGPT-o1, Towards Medical Complex Reasoning with LLMs](https://mlsanity.com/paper/2412.18925/) (2024)
- [Specializing Smaller Language Models towards Multi-Step Reasoning](https://mlsanity.com/paper/2301.12726/) (2023)
- [Imitate, Explore, and Self-Improve: A Reproduction Report on Slow-thinking Reasoning Systems](https://mlsanity.com/paper/2412.09413/) (2024)
- [Competitive Programming with Large Reasoning Models](https://mlsanity.com/paper/2502.06807/) (2025)
- [MedReason: Eliciting Factual Medical Reasoning Steps in LLMs via Knowledge Graphs](https://mlsanity.com/paper/2504.00993/) (2025)
- [MedTrinity-25M: A Large-scale Multimodal Dataset with Multigranular Annotations for Medicine](https://mlsanity.com/paper/2408.02900/) (2024)
- [Scientific Large Language Models: A Survey on Biological & Chemical Domains](https://mlsanity.com/paper/2401.14656/) (2024)
- [Training a Scientific Reasoning Model for Chemistry](https://mlsanity.com/paper/2506.17238/) (2025)
- [STaRK: Benchmarking LLM Retrieval on Textual and Relational Knowledge Bases](https://mlsanity.com/paper/2404.13207/) (2024)
- [Graph-constrained Reasoning: Faithful Reasoning on Knowledge Graphs with Large Language Models](https://mlsanity.com/paper/2410.13080/) (2024)
- [Self-Polish: Enhance Reasoning in Large Language Models via Problem Refinement](https://mlsanity.com/paper/2305.14497/) (2023)

## Built on by (most cited first, 2 of 2)

- [Knowledge before Reasoning: EC-Reason-Bench, a Training-Free Diagnostic Benchmark for LLM Enzyme Classification](https://mlsanity.com/paper/2607.26397/) (2026)
- [PertMind: Eliciting Emergent Biological Reasoning in LLM via Reinforcement Learning on Cellular Perturbation Data](https://mlsanity.com/paper/2608.16419/) (2026)

## Abstract (arXiv)

Understanding complex biomolecular mechanisms requires multi-step reasoning across molecular interactions, signaling cascades, and metabolic pathways. While large language models(LLMs) show promise in such tasks, their application to biomolecular problems is hindered by logical inconsistencies and the lack of grounding in domain knowledge. Existing approaches often exacerbate these issues: reasoning steps may deviate from biological facts or fail to capture long mechanistic dependencies. To address these challenges, we propose a Knowledge-Augmented Long-CoT Reasoning framework that integrates LLMs with knowledge graph-based multi-hop reasoning chains. The framework constructs mechanistic chains via guided multi-hop traversal and pruning on the knowledge graph; these chains are then incorporated into supervised fine-tuning to improve factual grounding and further refined with reinforcement learning to enhance reasoning reliability and consistency. Furthermore, to overcome the shortcomings of existing benchmarks, which are often restricted in scale and scope and lack annotations for deep reasoning chains, we introduce PrimeKGQA, a comprehensive benchmark for biomolecular question answering. Experimental results on both PrimeKGQA and existing datasets demonstrate that although larger closed-source models still perform well on relatively simple tasks, our method demonstrates clear advantages as reasoning depth increases, achieving state-of-the-art performance on multi-hop tasks that demand traversal of structured biological knowledge. These findings highlight the effectiveness of combining structured knowledge with advanced reasoning strategies for reliable and interpretable biomolecular reasoning.