Atomically accurate de novo design of antibodies with RFdiffusion

Abstract Despite the central role that antibodies play in modern medicine, there is currently no method to design novel antibodies that bind a specific epitope entirely in silico . Instead, antibody discovery currently relies on animal immunization or random library screening approaches. Here, we demonstrate that combining computational protein design using a fine-tuned RFdiffusion network alongside yeast display screening enables the generation of antibody variable heavy chains (VHHs) and single chain variable fragments (scFvs) that bind user-specified epitopes with atomic-level precision. To verify this, we experimentally characterized VHH binders to four disease-relevant epitopes using multiple orthogonal…

• NS
  National Science Foundation

  Awards: EF-2021552, T32GM008268, 2021552
• UD
  U.S. Department of Energy

  Awards: COVID-19, DE-SC0018940
• BA
  Bill and Melinda Gates Foundation

  Award: INV-010680
• WR
  Washington Research Foundation
• A
  Amgen
• CH
  Children's Hospital of Philadelphia
• OP
  Open Philanthropy Project
• NE
  National Energy Research Scientific Computing Center
• HF
  Hospital for Sick Children
• IF
  Institute for Basic Science

  Award: IBS-R030-C1
• NI
  National Institutes of Health

  Awards: T32GM008268, COVID-19, U19 AG065156
• OO
  Office of Science

  Awards: DE-SC0018940 MOD03, DE-SC0018940
• NI
  National Institute of General Medical Sciences

  Award: T32GM008268