Peer-Reviewed Publication
bioRxiv2025September 29, 2025Journal Article
Computational design of pH-sensitive binders.
Green Ahn1,2,3, Brian Coventry1,2,3, Ella Haefner1,2, Shayan Sadre1,4, Jenny Hu1,5, Mimosa Van1,6, Buwei Huang1,7, Isaac Sappington1,2,8, Adam J Broerman1,2,9, Mauriz A Lichtenstein1,10, Matthias Glögl1,2, Inna Goreshnik1,2,3, Dionne Vafeados1,2,3, David Baker1,2,3
1Institute for Protein Design, University of Washington, Seattle, WA, USA.
2Department of Biochemistry, University of Washington, Seattle, WA, USA.
3Howard Hughes Medical Institute, Seattle, WA, USA.
4Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA.
5Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
6Department of Biochemistry and Molecular Biology, Hamilton College, Clinton, NY, USA.
7Xaira Therapeutics, South San Francisco, CA, USA.
8Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA, USA.
9Department of Chemical Engineering, University of Washington, Seattle, WA, USA.
10Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Abstract
pH gradients are central to physiology, from vesicle acidification to the acidic tumor microenvironment. While therapeutics have been developed to exploit these pH changes to modulate activity across different physiological environments, current approaches for generating pH-dependent binders, such as combinatorial histidine scanning and display-based selections, are largely empirical and often lab…
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