Journal Article

PUBDB-2026-00766

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Improved protein binder design using β-pairing targeted RFdiffusion

Sappington, I. ; Toul, M. ; Lee, D. S. ; Robinson, S. A. ; Goreshnik, I. ; McCurdy, C. ; Chan, T. C. ; Buchholz, N. ; Huang, B. ; Vafeados, D. ; Garcia-Sanchez, M. ; Roullier, N. ; Glögl, M. ; Kim, C. J. ; Watson, J. L. ; Torres, S. V. ; Verschueren, K. H. G. ; Verstraete, K. ; Hinck, C. S. ; Benard-Valle, M. ; Coventry, B. ; Sims, J. N. ; Ahn, G. ; Wang, X. ; Hinck, A. P. ; Jenkins, T. P. ; Ruohola-Baker, H. ; Banik, S. M. ; Savvides, S. N. ; Baker, D. (Corresponding author)Extern*XFEL.EU*

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-67866-3  doi:10.3204/PUBDB-2026-00766

Abstract: 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2026

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