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AI-redesigned enzymes proved better starting points for directed evolution

Researchers used ProteinMPNN to redesign three botulinum-neurotoxin proteases, then compared evolution campaigns starting from redesigned or natural enzymes. Redesigned starting points repeatedly accessed higher-activity variants; an evolved BoNT/E protease achieved more than 79-fold greater selected specificity for ataxin-2 than the best comparator evolved from the natural enzyme.

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Stable ID
science-2026-ai-redesign-protein-evolution
Revision
science-2026-ai-redesign-protein-evolution.v1
Field
Biology and Biotechnology · AI-assisted protein engineering
Evidence
Tier 2 · Peer reviewed: Yes
Record state
Current · Peer-reviewed experimental result
Last checked

AI role

ProteinMPNN supplied substantive sequence redesigns that were then built, evolved and tested experimentally. The study also compared a physics-based PROSS redesign, so its conclusions do not rest on model predictions alone.

Record details

Problem or result
Natural proteins often lose stability or activity while accumulating mutations needed for a new laboratory-evolved function
Authors
Nicholas A. Krasnow, Joy A. Xu, Emily Zhang, Gandhar K. Mahadeshwar, David R. Liu et al.
Institutions
Broad Institute, Harvard University, Howard Hughes Medical Institute and collaborators
Result date
Published July 22, 2026

Why it matters

Combining model-guided sequence redesign with continuous laboratory evolution expands the mutation space that enzymes can tolerate and offers a general route to proteins with new functions.

Limits

This is a protein-engineering demonstration, not a therapy. The ataxin-2-cleaving proteases were characterized in biochemical assays and transfected cells; delivery, organism-level efficacy, immunogenicity, safety and unintended substrates were not established.

Sources

  1. Primary: Nature, AI-redesigned starting points and outcomes enhance protein evolution
  2. Independent: Howard Hughes Medical Institute profile and PACE research context

Correction and revision history

  1. 2026-07-23 — Added after checking the final open-access Nature article, side-by-side evolution design, reported specificity result and preclinical limits.

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