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| Main Authors: | , , , , , , |
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| Format: | Preprint |
| Published: |
2025
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| Subjects: | |
| Online Access: | https://arxiv.org/abs/2512.02315 |
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Table of Contents:
- Accurately predicting protein fitness with minimal experimental data is a persistent challenge in protein engineering. We introduce PRIMO (PRotein In-context Mutation Oracle), a transformer-based framework that leverages in-context learning and test-time training to adapt rapidly to new proteins and assays without large task-specific datasets. By encoding sequence information, auxiliary zero-shot predictions, and sparse experimental labels from many assays as a unified token set in a pre-training masked-language modeling paradigm, PRIMO learns to prioritize promising variants through a preference-based loss function. Across diverse protein families and properties-including both substitution and indel mutations-PRIMO outperforms zero-shot and fully supervised baselines. This work underscores the power of combining large-scale pre-training with efficient test-time adaptation to tackle challenging protein design tasks where data collection is expensive and label availability is limited.