VIB-VUB: Imperfection Improves Membrane Protein Folding
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- VIB-VUB Center for Structural Biology researchers published in PNAS that a 'negative design' strategy — adding subtle destabilizing features to synthetic transmembrane β-barrel proteins — enables them to fold and assemble in artificial membranes.
- First author Giacomo Pedrelli explained that traditional stability-maximizing designs become 'too eager to fold too early,' causing the proteins to aggregate in water before ever reaching the membrane.
- The destabilizing tweaks reduced aggregation and significantly improved membrane insertion and assembly, without substantially compromising the final stability of the folded proteins.
- AI protein language model ESM3, trained on evolutionary data, outperformed conventional physics-based tools by pinpointing negative design mutations that traditional methods had flagged as harmful.
- Senior author Prof. Anastassia Vorobieva (VIB-VUB) said the work shows researchers must 'think beyond static structures' and consider the entire folding journey, opening paths to designing nanopores for biosensing, molecular detection, and next-generation sequencing.
Why it matters: This overturns a core assumption in protein engineering — that maximizing stability is the design target — and shows an AI model (ESM3) outperforming physics-based tools at identifying the right mutations. Biotech and synthetic biology teams building custom membrane proteins for nanopore sequencing and biosensing now have a concrete design principle to apply to a class of proteins notoriously resistant to engineering.
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