I’m extremely fortunate to work with a fantastic team - Shayan Sadre, Ella Haefner, and Brian Coventry and all authors at @uwproteindesign.bsky.social with support from David Baker. This work would not have been possible without them!

Programmable pH-sensitivity enables building conditional control into protein-based therapeutics, diagnostics, and synthetic biology tools.

These methods identified key principles for designing pH sensitivity, enabling the development of pH-dependent binders against several disease-relevant targets and their application in catalytic extracellular protein degradation.

and (ii) engineer buried charged networks inside the binder to destabilize the binder while preserving the interface residues.

We combined Rosetta and deep-learning based methods to (i) weaken the binder-target interface by inducing electrostatic repulsion upon histidine protonation