Generative AI designs de novo thiolation domains that boost nrps yields up to ~3‑fold

Across the experiments, many AI‑designed T‑domains supported peptide production, and the top performers raised product titers by roughly three times compared with the native T‑domain. A representative design, called AI‑2, also displayed improved biochemical properties: higher soluble expression, efficient refolding and a melting temperature about 12 °C above the wild‑type carrier. Molecular dynamics simulations suggested that while overall fold stability was retained, the engineered domains reshaped state‑dependent interdomain contact networks, explaining their context‑dependent activity.

The work demonstrates that generative protein models can engineer dynamic, multi‑domain enzymes whose function depends on transient interfaces, offering a new route for reprogramming biosynthetic assembly lines and expanding the toolkit for synthetic biology and drug discovery.