Reference-guided Policy Optimization for Molecular Optimization via LLM Reasoning

TL;DR

This paper introduces RePO, a novel reference-guided policy optimization method that enhances molecular optimization with LLMs by balancing exploration and exploitation, outperforming existing fine-tuning and reinforcement learning approaches.

Contribution

RePO is a new optimization approach that learns from reference molecules without trajectory data, combining RL exploration with supervised guidance for improved molecular optimization.

Findings

RePO outperforms SFT and RLVR baselines on benchmarks.

RePO achieves higher success rate and similarity scores.

RePO generalizes better to unseen instruction styles.

Abstract

Large language models (LLMs) benefit substantially from supervised fine-tuning (SFT) and reinforcement learning with verifiable rewards (RLVR) in reasoning tasks. However, these recipes perform poorly in instruction-based molecular optimization, where each data point typically provides only a single optimized reference molecule and no step-by-step optimization trajectory. We reveal that answer-only SFT on the reference molecules collapses reasoning, and RLVR provides sparse feedback under similarity constraints due to the model's lack of effective exploration, which slows learning and limits optimization. To encourage the exploration of new molecules while balancing the exploitation of the reference molecules, we introduce Reference-guided Policy Optimization (RePO), an optimization approach that learns from reference molecules without requiring trajectory data. At each update, RePO samples candidate molecules with their intermediate reasoning trajectories from the model and trains the model using verifiable rewards that measure property satisfaction under similarity constraints in an RL manner. Meanwhile, it applies reference guidance by keeping the policy's intermediate reasoning trajectory as context and training only the answer in a supervised manner. Together, the RL term promotes exploration, while the guidance term mitigates reward sparsity and stabilizes training by grounding outputs to references when many valid molecular edits exist. Across molecular optimization benchmarks, RePO consistently outperforms SFT and RLVR baselines (e.g., GRPO), achieving improvements on the optimization metric (Success Rate $\times$ Similarity), improving balance across competing objectives, and generalizing better to unseen instruction styles. Our code is publicly available at https://github.com/tmlr-group/RePO.