Protein Design with Agent Rosetta: A Case Study for Specialized Scientific Agents

Computer Science > Artificial Intelligence [Submitted on 16 Mar 2026] Protein Design with Agent Rosetta: A Case Study for Specialized Scientific Agents Jacopo Teneggi, S.M. Bargeen A. Turzo, Tanya Marwah, Alberto Bietti, P. Douglas Renfrew, Vikram Khipple Mulligan, Siavash Golkar Large language models (LLMs) are capable of emulating reasoning and using tools, creating opportunities for autonomous agents that execute complex scientific tasks. Protein design provides a natural testbed: although machine learning (ML) methods achieve strong results, these are largely restricted to canonical amino acids and narrow objectives, leaving unfilled need for a generalist tool for broad design pipelines. We introduce Agent Rosetta, an LLM agent paired with a structured environment for operating Rosetta, the leading physics-based heteropolymer design software, capable of modeling non-canonical building blocks and geometries. Agent Rosetta iteratively refines designs to achieve user-defined objectives, combining LLM reasoning with Rosetta's generality. We evaluate Agent Rosetta on design with canonical amino acids, matching specialized models and expert baselines, and with non-canonical residues -- where ML approaches fail -- achieving comparable performance. Critically, prompt engineering alone often fails to generate Rosetta actions, demonstrating that environment design is essential for integrating LLM agents with specialized software. Our results show that properly designed environments enable LLM agents to make scientific software accessible while matching specialized tools and human experts. Subjects: Artificial Intelligence (cs.AI) Cite as: arXiv:2603.15952 [cs.AI]   (or arXiv:2603.15952v1 [cs.AI] for this version)   https://doi.org/10.48550/arXiv.2603.15952 Focus to learn more Submission history From: Jacopo Teneggi [view email] [v1] Mon, 16 Mar 2026 22:06:03 UTC (9,640 KB) Access Paper: HTML (experimental) view license Current browse context: cs.AI < prev   |   next > new | recent | 2026-03 Change to browse by: cs References & Citations NASA ADS Google Scholar Semantic Scholar Export BibTeX Citation Bookmark Bibliographic Tools Bibliographic and Citation Tools Bibliographic Explorer Toggle Bibliographic Explorer (What is the Explorer?) Connected Papers Toggle Connected Papers (What is Connected Papers?) Litmaps Toggle Litmaps (What is Litmaps?) scite.ai Toggle scite Smart Citations (What are Smart Citations?) Code, Data, Media Demos Related Papers About arXivLabs Which authors of this paper are endorsers? | Disable MathJax (What is MathJax?)