EPFL team uses RFdiffusion to design de novo metamorphic proteins switching between two folds
ferruz_noelia · x · 2026-10-16
EPFL's Correia lab published a bioRxiv study computationally designing de novo metamorphic proteins: single sequences that populate two distinct, well-folded conformations without any external trigger.
Key method and findings:
- Starting from 93 small natural domains (60–150 aa), they used RFdiffusion to remodel termini while keeping cores fixed, generating 200 alternative conformations per domain and selecting pairs with RMSD >4 Å and ≥40% secondary-structure change
- Notable observation: large structural changes need only modest sequence changes — many alternative-state designs retained >50% sequence identity despite structural differences up to 16 Å RMSD
- State-defining mutations bias the energy landscape toward State 1 or State 2, enabling controllable conformational switching
The work charts a path from designing single static structures toward designing controllable protein conformational landscapes.
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