Enzymes with working catalytic machinery designed from scratch
Diffusion-based protein design produced serine hydrolases with catalytic efficiencies up to 2.2 × 10⁵ M⁻¹s⁻¹ on five folds unlike any natural serine hydrolase, with crystal structures matching the design models to under 1 Å.
- Model
- RFdiffusion with PLACER ensemble scoring
- Field
- Chemistry
- Date
- 2025-02-13
- Human collaborators
- Anna Lauko, David Baker
Sources
Original work
Announcement
What was found
An enzyme needs more than the right shape: its active site has to stay organised at every step of the reaction, which is where designed enzymes have historically failed. The team generated backbones with RFdiffusion from a minimal active-site description, then used an ensemble-generation network to check that the catalytic geometry held along the whole reaction coordinate, keeping only designs that passed. The resulting hydrolases approach natural catalytic efficiency on folds not found among natural serine hydrolases, and the crystal structures match the designs closely. Published in Science.
Novelty check
De novo enzyme design dates to the 2000s (Kemp eliminases, retro-aldolases), but designed enzymes were typically orders of magnitude slower than natural ones and needed directed evolution to become useful. The advance is reaching this efficiency with multi-step catalytic machinery by design rather than by evolution.
Caveats and known objections
Serine hydrolases are a comparatively tractable target with a well-understood catalytic triad; the result does not generalise automatically to harder chemistry. Efficiencies remain below the best natural hydrolases. The per-round success rate is low and the paper reports the screening funnel. The reaction, the active-site description and the assays were human-specified, which is why autonomy is search-scaffold.
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Entry history (1 event)
- AddedEntered the registry graded Peer reviewed and Search scaffold.
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Graded peer reviewed for verification and search scaffold for autonomy. What these mean.
Cite this entry
whataifound.org. (2025). Enzymes with working catalytic machinery designed from scratch. whataifound.org: A Registry of AI Scientific and Mathematical Discoveries. https://whataifound.org/finding/2025-02-13-designed-serine-hydrolasesBibTeX
@misc{whataifound-instituteforproteindesign-2025-hydrolases,
title = {Enzymes with working catalytic machinery designed from scratch},
author = {{whataifound.org}},
year = {2025},
howpublished = {whataifound.org: A Registry of AI Scientific and Mathematical Discoveries},
note = {Result by Institute for Protein Design, University of Washington. Verification: Peer reviewed. Autonomy: Search scaffold.},
url = {https://whataifound.org/finding/2025-02-13-designed-serine-hydrolases}
}