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Two-Stage Fine-Tuning for Protein Sequence Generation with Targeted Amino-Acid Composition

arXiv 2606.27939 ↗First posted 26 Jun 2026cs.LG cs.AI q-bio.BMcited by 0

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Abstract (arXiv)

Protein language models are standard priors for biological sequence generation, but steering them toward explicit distributional design targets remains largely unexplored. We study a constrained protein generation problem in which sequences must match a desired amino-acid (AA) composition profile while preserving plausible sequence statistics and diversity. The motivating application is synthetic feed protein design, where the AA composition of dietary proteins directly determines their nutritional value. We propose a two-stage pipeline in which domain-adaptive fine-tuning (FT) on an in-domain protein dataset is followed by iterative reward-weighted FT via reinforcement learning (RL) anchored against the FT model as a frozen reference. We evaluate the pipeline on two AA compositions and find that FT brings the average composition close to the target, while the subsequent RL enforces specific sequence constraints that FT alone cannot satisfy. We additionally evaluate the design choices of the proposed composition reward term against two baselines and an ablated variant, isolate the contribution of each training stage, and verify that AA composition alignment is achieved without degrading sequence quality.

Key facts. No citing papers in the map yet (data through 14 Oct 2026). Builds on 7 of its 20 references that are in the map. First posted on arXiv 26 Jun 2026.

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References · 7

  1. 2023Direct Preference Optimization: Your Language Model is Secretly a Reward Modelcited by 8,065
  2. 2020Don't Stop Pretraining: Adapt Language Models to Domains and Taskscited by 1,565
  3. 2019Advantage-Weighted Regression: Simple and Scalable Off-Policy Reinforcement Learningcited by 782
  4. 2022ProGen2: Exploring the Boundaries of Protein Language Modelscited by 159
  5. 2022RITA: a Study on Scaling Up Generative Protein Sequence Modelscited by 42
  6. 2024Reinforcement Learning for Sequence Design Leveraging Protein Language Modelscited by 1
  7. 2025A deep reinforcement learning platform for antibiotic discoverycited by 1

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  1. 2025Self Distillation Fine-Tuning of Protein Language Models Improves Versatility in Protein Design
  2. 2026Be Your Own Teacher: Steering Protein Language Models via Unsupervised Reward Optimization
  3. 2025From Supervision to Exploration: What Does Protein Language Model Learn During Reinforcement Learning?
  4. 2025Steering Generative Models with Experimental Data for Protein Fitness Optimization
  5. 2025Steering Protein Language Models
  6. 2025ProteinZero: Self-Improving Protein Generation via Online Reinforcement Learning
  7. 2024Diffusion on language model encodings for protein sequence generation
  8. 2026ProteinOPD: Towards Effective and Efficient Preference Alignment for Protein Design