AgentFold: Closed-Loop Agentic Search for Protein Folding Model Design

• URL: http://arxiv.org/abs/2608.26747v2
• Date: Fri, 28 Aug 2026 08:35:25 GMT
• Title: AgentFold: Closed-Loop Agentic Search for Protein Folding Model Design
• Abstract summary: We present AgentFold, a framework that formulates folding-model development as a closed-loop search over executable code variants.<n>Under a matched computational budget, AgentFold improves the best lDDT by 7.5% over independent Codex proposals.<n>The resulting intervention traces reveal recurring empirical design patterns.
• Score: 27.154390712714264
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Scientific LLM agents have shown promise in literature reasoning, tool use, and experiment planning, but it remains unclear whether they can autonomously improve large, tightly coupled scientific machine-learning systems through executable code changes and computationally expensive validation. We study this question in protein folding, where progress requires coordinated architectural modifications, multi-objective evaluation, and domain-aware interpretation. We present AgentFold, a multi-agent framework that formulates folding-model development as a closed-loop search over executable code variants. Starting from ESMFold, AgentFold proposes hypotheses, implements and debugs code-level modifications, evaluates model variants, analyzes experimental outcomes, and stores both successful and failed interventions in structured memory. An MCTS-style policy allocates computational resources across high-scoring search branches. On an engineering-scale protein-folding codebase comprising more than 2,000 lines of code, AgentFold explores approximately 80 model variants using approximately 5,000 GPU-hours and 170 million LLM tokens. Under a matched computational budget, AgentFold improves the best lDDT by 7.5% over independent Codex proposals and outperforms a random-search control. Beyond model improvement, the resulting intervention traces reveal recurring empirical design patterns: stable gains tend to arise from early, soft, learnable priors and gated refinement, whereas direct geometric perturbations and geometry-conditioned feedback often destabilize training. The code and experimental resources are publicly available at https://github.com/lmqfly/AgentFold.

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