%0 Journal Article
%A Sappington, Isaac
%A Toul, Martin
%A Lee, David S.
%A Robinson, Stephanie A.
%A Goreshnik, Inna
%A McCurdy, Clara
%A Chan, Tung Ching
%A Buchholz, Nic
%A Huang, Buwei
%A Vafeados, Dionne
%A Garcia-Sanchez, Mariana
%A Roullier, Nicole
%A Glögl, Matthias
%A Kim, Christopher J.
%A Watson, Joseph L.
%A Torres, Susana Vázquez
%A Verschueren, Koen H. G.
%A Verstraete, Kenneth
%A Hinck, Cynthia S.
%A Benard-Valle, Melisa
%A Coventry, Brian
%A Sims, Jeremiah Nelson
%A Ahn, Green
%A Wang, Xinru
%A Hinck, Andrew P.
%A Jenkins, Timothy P.
%A Ruohola-Baker, Hannele
%A Banik, Steven M.
%A Savvides, Savvas N.
%A Baker, David
%T Improved protein binder design using β-pairing targeted RFdiffusion
%J Nature Communications
%V 17
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M PUBDB-2026-00766
%P 1101
%D 2026
%X Designing proteins that bind with high affinity to hydrophilic protein target sites remains a challenging problem. Here we show that RFdiffusion can be conditioned to generate protein scaffolds that form geometrically matched extended β-sheets with target protein edge β-strands in which polar groups on the target are complemented with hydrogen bonding groups on the design. We use this approach to design binders against edge-strand target sites on KIT, PDGFRɑ, ALK-2, ALK-3, FCRL5, NRP1, and α-CTX, and obtain higher (pM to mid nM) affinities and success rates than unconditioned RFdiffusion. Despite sharing β-strand interactions, designs have high specificity, reflecting the precise customization of interacting β-strand geometry and additional designed binder-target interactions. A binder-KIT co-crystal structure is nearly identical to the design model, confirming the accuracy of the design approach. The ability to robustly generate binders to the hydrophilic interaction surfaces of exposed β-strands considerably increases the range of computational binder design.
%F PUB:(DE-HGF)16
%9 Journal Article
%R 10.1038/s41467-025-67866-3
%U https://bib-pubdb1.desy.de/record/646221