Generalizable and scalable protein stability prediction with rewired protein generative models

Predicting changes in protein thermostability caused by amino acid substitutions is essential for understanding human diseases and engineering proteins for practical applications. While recent protein generative models demonstrate impressive zero-shot performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability remains underexploited to improve protein stability prediction. We present SPURS, a deep learning framework that rewires and integrates two complementary protein generative models–a protein language model and an inverse folding model–and reprograms this unified framework for stability prediction through supervised fine-tuning on mega-scale thermostability data. SPURS delivers accurate, efficient, and scalable stability predictions with exceptional generalization to unseen proteins and mutations. Beyond stability prediction, SPURS enables broad applications in protein informatics, including zero-shot identification of functional residues, improved low- N protein fitness prediction, and systematic dissection of stability-pathogenicity for human diseases. Together, these capabilities establish SPURS as a versatile tool for advancing protein stability prediction and protein engineering at scale.