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.