PRIZM: Combining Low-N Data and Zero-shot Models to Design Enhanced Protein Variants

Abstract Machine learning has repeatedly shown the ability to accelerate protein engineering, but many approaches demand large amounts of robust, high-quality training data as well as substantial computational expertise. While large pre-trained models can function as zero-shot proxies for predicting variant effects, selecting the best model for a given protein property is often non-trivial. Here, we introduce Protein Ranking using Informed Zero-shot Modelling (PRIZM), a two-phase workflow that first uses a high-quality low-N dataset to identify the most suitable pre-trained zero-shot model for a target protein property and then applies that model to rank and prioritize an in silico variant library for experimental testing. Across diverse benchmark datasets spanning multiple protein properties, PRIZM reliably separated low- from high-performing models using datasets of ∼20 labelled variants. We further demonstrate PRIZM in enzyme engineering case studies targeting sucrose synthase thermostability and glycosyltransferase activity, where PRIZM-guided selection identified improved variants, including gains of ∼3°C in apparent melting temperature and ∼20% higher relative activity. PRIZM provides an accessible, data-efficient route to leverage foundation models for protein design while requiring minimal experimental data.