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<p>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.</p>

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Improved protein binder design using β-pairing targeted RFdiffusion

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月10日

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  • Isaac Sappington,
  • Martin Toul,
  • David S. Lee,
  • Stephanie A. Robinson,
  • Inna Goreshnik,
  • Clara McCurdy,
  • Tung Ching Chan,
  • Nic Buchholz,
  • Buwei Huang,
  • Dionne Vafeados,
  • Mariana Garcia-Sanchez,
  • Nicole Roullier,
  • Matthias Glögl,
  • Christopher J. Kim,
  • Joseph L. Watson,
  • Susana Vázquez Torres,
  • Koen H. G. Verschueren,
  • Kenneth Verstraete,
  • Cynthia S. Hinck,
  • Melisa Benard-Valle,
  • Brian Coventry,
  • Jeremiah Nelson Sims,
  • Green Ahn,
  • Xinru Wang,
  • Andrew P. Hinck,
  • Timothy P. Jenkins,
  • Hannele Ruohola-Baker,
  • Steven M. Banik,
  • Savvas N. Savvides,
  • David Baker

摘要

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.