Iterative computational and rational design generates diverse PET hydrolases for plastic depolymerization.

Thermobifida fusca TfCut2 is the most design-amenable PETase scaffold, and iterative EVdesign plus four rational mutations yields improved PET hydrolase activity.

• Why it matters: PET plastic depolymerization needs enzymes with higher and more diverse performance, but scaling amino-acid exploration while retaining function is difficult.
• What they did: The team combined EVdesign with rational design and experimentally tested 603 PETase designs from eight parent PETases, including variants with 12–68 substitutions.
• The result: Over 400 variants depolymerized PET and nearly all outperformed their parents, with many approaching LCC-ICCG benchmark performance in partial conversion assays.

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