Optimizing protein design through uncertainty-weighted steering of protein language models

Abstract

Abstract Motivation Protein Language Models (PLMs) have revolutionized protein engineering by capturing the evolutionary constraints inherent in natural protein sequences. However, precisely steering these models to engineer novel proteins with targeted functionalities remains challenging due to the inherent difficulty in modifying their latent representations considering the design objectives. Recently, activation steering of PLMs has emerged as a potent, training-free intervention for directing PLM outputs. However, the requirement for high-quality labeled datasets limits its application. In data-scarce or out-of-distribution (OOD) regimes, researchers must rely on surrogate models for label prediction; however, deterministic surrogates fail to account for the underlying uncertainty, often yielding steering vectors that result in suboptimal protein design. Results To address this, we propose PROSOUNDS (PROtein Sequence Optimization through UNcertainty-weighteD Steering), a PLM-based protein design framework that integrates uncertainty quantification into the activation steering logic. By weighting the steering activation calculation process based on uncertainty estimates of the surrogate predictions, PROSOUNDS enables robust protein optimization through precise mutational design even in the absence of ground-truth labels. Comprehensive performance evaluation reveals that PROSOUNDS consistently outperforms deterministic alternatives across three different protein property optimization tasks. Availability and Implementation The datasets and implementation code for PROSOUNDS are available at https://github.com/TeresaZhouTamu/PRO-SOUNDS.