Protein Language Model Fitness is a Matter of Preference
Cade W Gordon Amy X. Lu Pieter Abbeel
Leveraging billions of years of evolution, scientists have trained protein language models (pLMs) to understand the sequence and structure space of proteins aiding in the design of more functional proteins. Although they have shown ability to improve efficiency in engineering, it remains unclear under what conditions they will succeed or fail. We aim to predict the circumstances in which pLMs can successfully perform zero-shot fitness estimation. Our work demonstrates the trends observed over hundreds of deep mutational scans across multiple different fitness objectives. We find that the likelihood, or abstractly, implicit preference of a certain protein sequence imbued during pretraining is predictive fitness prediction capabilities. Both over-preferred and under-preferred wild type sequences harm performance. Generating a causal link between training data and likelihood, we show a power law tail over what data increases protein likelihood which is tied to training sequence homology. Lastly, proteins of low likelihood can be remedied by unsupervised finetuning. In sum, the zero-shot fitness estimation abilities of pLMs can be predicted by the likelihood of the engineered sequence, thus suggesting when pLMs should be deployed in protein maturation campaigns and a way to improve their performance under circumstances of low likelihood.
protein language models, zero-shot fitness prediction