# Boosting In-Silicon Directed Evolution with Fine-Tuned Protein Language Model and Tree Search

arXiv: https://arxiv.org/abs/2511.09900 · HTML: https://mlsanity.com/paper/2511.09900/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 15 of its 63 references that are in the map.
- First posted on arXiv 13 Nov 2025.

## Builds on (most cited first, 15 of 15)

- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [Proximal Policy Optimization Algorithms](https://mlsanity.com/paper/1707.06347/) (2017)
- [RoBERTa: A Robustly Optimized BERT Pretraining Approach](https://mlsanity.com/paper/1907.11692/) (2019)
- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Language Agent Tree Search Unifies Reasoning Acting and Planning in Language Models](https://mlsanity.com/paper/2310.04406/) (2023)
- [rStar-Math: Small LLMs Can Master Math Reasoning with Self-Evolved Deep Thinking](https://mlsanity.com/paper/2501.04519/) (2025)
- [Evaluating Protein Transfer Learning with TAPE](https://mlsanity.com/paper/1906.08230/) (2019)
- [OctoPack: Instruction Tuning Code Large Language Models](https://mlsanity.com/paper/2308.07124/) (2023)
- [Conditioning by adaptive sampling for robust design](https://mlsanity.com/paper/1901.10060/) (2019)
- [AdaLead: A simple and robust adaptive greedy search algorithm for sequence design](https://mlsanity.com/paper/2010.02141/) (2020)
- [Med42 -- Evaluating Fine-Tuning Strategies for Medical LLMs: Full-Parameter vs. Parameter-Efficient Approaches](https://mlsanity.com/paper/2404.14779/) (2024)
- [Design by adaptive sampling](https://mlsanity.com/paper/1810.03714/) (2018)
- [Steering Generative Models with Experimental Data for Protein Fitness Optimization](https://mlsanity.com/paper/2505.15093/) (2025)
- [Tree Search-Based Evolutionary Bandits for Protein Sequence Optimization](https://mlsanity.com/paper/2401.06173/) (2024)

## Built on by (most cited first, 1 of 1)

- [Linear Fitness Subspace in Protein Language Models Enables Sample-Efficient Directed Evolution](https://mlsanity.com/paper/2610.07607/) (2026)

## Abstract (arXiv)

Protein evolution through amino acid mutations is a cornerstone of life sciences. Recent advances in protein language models have shown rich evolutionary patterns, offering unprecedented potential for in-silicon directed evolution. However, existing directed evolution methods largely rely on heuristic evolution strategies and have yet to efficiently integrate the transformative protein language models with advanced optimization techniques, such as reinforcement learning, to adaptively learn superior evolution policies. To bridge this gap, we propose AlphaDE, a novel framework that evolves protein sequences by harnessing the innovative paradigms of large language models, such as fine-tuning and test-time inference. First, AlphaDE fine-tunes pretrained protein language models using masked language modeling on homologous protein sequences to activate the evolutionary plausibility of the interested protein family. Second, AlphaDE introduces test-time inference based on Monte Carlo tree search, which effectively evolves proteins with evolutionary guidance from the fine-tuned protein language model. Extensive benchmark experiments show that AlphaDE remarkably outperforms previous state-of-the-art methods even with few-shot fine-tuning. A case study further demonstrates that AlphaDE supports condensing the protein sequence space of avGFP through computational evolution.