Generative steering to adapt proteins beyond native biological contexts

ProVADA enables functional protein redesign, converting human renin into an active cytosolic protease and deimmunizing murine antibodies with significant HLA-I binder reduction.

• Why it matters: Adapting proteins for new cellular or therapeutic environments is challenging because native proteins often fail outside their original contexts, limiting their utility.
• What they did: ProVADA, a test-time framework, uses Mixture-Adaptation Directed Annealing to steer pretrained protein generators through coordinated mutations, population selection, and annealing, targeting desired properties.
• The result: The approach successfully transformed human renin and deimmunized murine antibodies, reducing HLA visibility while maintaining function, demonstrating broad sequence redesign's potential for context adaptation.