# InstructPro2: Natural Language and Biological Grounding Guided De Novo Protein Design

arXiv: https://arxiv.org/abs/2610.19592 · HTML: https://mlsanity.com/paper/2610.19592/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 15 of its 47 references that are in the map.
- First posted on arXiv 14 Oct 2026.

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

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Training language models to follow instructions with human feedback](https://mlsanity.com/paper/2203.02155/) (2022)
- [Exploring the Limits of Transfer Learning with a Unified Text-to-Text Transformer](https://mlsanity.com/paper/1910.10683/) (2019)
- [Flamingo: a Visual Language Model for Few-Shot Learning](https://mlsanity.com/paper/2204.14198/) (2022)
- [Self-Instruct: Aligning Language Models with Self-Generated Instructions](https://mlsanity.com/paper/2212.10560/) (2022)
- [Instruction-Following Evaluation for Large Language Models](https://mlsanity.com/paper/2311.07911/) (2023)
- [Domain-Specific Language Model Pretraining for Biomedical Natural Language Processing](https://mlsanity.com/paper/2007.15779/) (2020)
- [SpanBERT: Improving Pre-training by Representing and Predicting Spans](https://mlsanity.com/paper/1907.10529/) (2019)
- [ChemBERTa: Large-Scale Self-Supervised Pretraining for Molecular Property Prediction](https://mlsanity.com/paper/2010.09885/) (2020)
- [ProGen2: Exploring the Boundaries of Protein Language Models](https://mlsanity.com/paper/2206.13517/) (2022)
- [Iterative Refinement Graph Neural Network for Antibody Sequence-Structure Co-design](https://mlsanity.com/paper/2110.04624/) (2021)
- [A Text-guided Protein Design Framework](https://mlsanity.com/paper/2302.04611/) (2023)
- [InstructProtein: Aligning Human and Protein Language via Knowledge Instruction](https://mlsanity.com/paper/2310.03269/) (2023)
- [Scaling Atomistic Protein Binder Design with Generative Pretraining and Test-Time Compute](https://mlsanity.com/paper/2603.27950/) (2026)
- [InstructPro: Natural Language Guided Ligand-Binding Protein Design](https://mlsanity.com/paper/2506.09332/) (2025)

## Abstract (arXiv)

The ability to generate proteins with desired functions is a central goal of computational biology. Although natural language can express diverse design objectives, existing protein generation methods often support only narrow tasks or make limited use of biological constraints. We develop InstructPro2 to translate natural-language design objectives into protein sequences while incorporating task-specific biological context. A text encoder captures the design instructions, while dedicated ligand and antigen encoders provide biological context to the sequence-generating decoder. For pretraining, we assemble InstructPro2Bench, comprising 205.7 million <function description, protein> pairs from UniProtKB. We subsequently adapt the model to ligand-binding protein and antibody design. On functional protein generation benchmarks, InstructPro2 outperforms Pinal, the strongest baseline, achieving a functional recovery F1 of 74.8 versus 62.2 and lowering global RMSD from 5.33A to 3.04A. For antibody design, the model obtains a DockQ score of 0.39, while ligand-binding protein design reaches a docking success rate of 72.6%. These findings highlight how integrating language-based instructions with biological conditioning can extend protein generation to distinct design settings.