These results show how much we still need to learn about membrane protein folding & protein–lipid interactions. Proud of Giacomo’s persistence in pushing boundaries!

Surprisingly, mutations that would be catastrophic in soluble proteins (e.g. valine → proline) can actually yield well-folded, thermostable membrane proteins.

Negative design mutations (predicted to improve fitness but destabilizing the native state) can rescue poorly folding designs.

The classic “native state optimization” paradigm in de novo design drives our designs to aggregate, showing it’s not enough for membrane proteins.

Negative design enables cell-free expression and folding of designed transmembrane β-Barrels De novo design of membrane proteins (MPs) is a rapidly growing field with transformative potential for synthetic biology. Yet, progress has lagged behind that of soluble proteins, largely due to limit...

Very proud to share the first-author work from my first PhD student, Giacomo Pedrelli 🎉. He combined cell-free expression and computational design to explore how transmembrane β-barrels fold – and what that means for designing them from scratch.

www.biorxiv.org/content/10.1...

Key findings 🧵👇