AI-designed starting points accelerate enzyme evolution for enhanced stability and precision

A Nature study shows that AI-designed, stabilized BoNT proteases (via ProteinMPNN) used as starting points for phage-assisted continuous evolution (PACE/PANCE) consistently yield enzymes with higher stability, better soluble expression, and greater catalytic efficiency across substrates than wild-type starts. Redesigned starting points expand the mutationally accessible sequence space, enabling faster adaptation and access to high-function genotypes that WT enzymes cannot reach. Notably, redesigned BoNT/E variants evolved to specifically cleave disease-relevant ataxin-2 with substantially higher specificity and minimal native-substrate activity, illustrating a practical AI-plus-evolution workflow to rapidly reprogram enzymes for new targets with improved safety profiles.