One-shot design of functional protein binders with BindCraft

Martin Pacesa (), Lennart Nickel, Christian Schellhaas, Joseph Schmidt, Ekaterina Pyatova, Lucas Kissling, Patrick Barendse, Jagrity Choudhury, Srajan Kapoor, Ana Alcaraz-Serna, Yehlin Cho, Kourosh H. Ghamary, Laura Vinué, Brahm J. Yachnin, Andrew M. Wollacott, Stephen Buckley, Adrie H. Westphal, Simon Lindhoud, Sandrine Georgeon, Casper A. Goverde, Georgios N. Hatzopoulos, Pierre Gönczy, Yannick D. Muller, Gerald Schwank, Daan C. Swarts, Alex J. Vecchio, Bernard L. Schneider, Sergey Ovchinnikov () and Bruno E. Correia ()
Additional contact information
Martin Pacesa: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Lennart Nickel: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Christian Schellhaas: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Joseph Schmidt: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Ekaterina Pyatova: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Lucas Kissling: University of Zurich
Patrick Barendse: Wageningen University
Jagrity Choudhury: University at Buffalo
Srajan Kapoor: University at Buffalo
Ana Alcaraz-Serna: Lausanne University Hospital and University of Lausanne
Yehlin Cho: Massachusetts Institute of Technology
Kourosh H. Ghamary: Visterra Inc.
Laura Vinué: Visterra Inc.
Brahm J. Yachnin: Visterra Inc.
Andrew M. Wollacott: Visterra Inc.
Stephen Buckley: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Adrie H. Westphal: Wageningen University
Simon Lindhoud: Wageningen University
Sandrine Georgeon: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Casper A. Goverde: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Georgios N. Hatzopoulos: Swiss Federal Institute of Technology Lausanne (EPFL)
Pierre Gönczy: Swiss Federal Institute of Technology Lausanne (EPFL)
Yannick D. Muller: Lausanne University Hospital and University of Lausanne
Gerald Schwank: University of Zurich
Daan C. Swarts: Wageningen University
Alex J. Vecchio: University at Buffalo
Bernard L. Schneider: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Sergey Ovchinnikov: Massachusetts Institute of Technology
Bruno E. Correia: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics

Nature, 2025, vol. 646, issue 8084, 483-492

Abstract: Abstract Protein–protein interactions are at the core of all key biological processes. However, the complexity of the structural features that determine protein–protein interactions makes their design challenging. Here we present BindCraft, an open-source and automated pipeline for de novo protein binder design with experimental success rates of 10–100%. BindCraft leverages the weights of AlphaFold2 (ref. 1) to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, de novo designed proteins and multi-domain nucleases, such as CRISPR–Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Last, we use cell-surface-receptor-specific binders to redirect adeno-associated virus capsids for targeted gene delivery. This work represents a significant advancement towards a ‘one design-one binder’ approach in computational design, with immense potential in therapeutics, diagnostics and biotechnology.

Date: 2025
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DOI: 10.1038/s41586-025-09429-6

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