One-shot design of functional protein binders with BindCraft

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. <sup>1</sup>) 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.

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Publication Details

Journal
Nature
Published
2025-08-27
DOI
https://doi.org/10.1038/s41586-025-09429-6
Citations
98
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
133.30
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article

One-shot design of functional protein binders with BindCraft

Bernard L. Schneider, Yannick D. Müller, Adrie H. Westphal, Andrew M. Wollacott et al.
98 citations
Nature
Monoclonal and Polyclonal Antibodies Research
133.30
article

One-shot design of functional protein binders with BindCraft

Bernard L. Schneider, Yannick D. Müller, Adrie H. Westphal, Andrew M. Wollacott, Lennart Nickel, Stephen Buckley, Gerald Schwank, Pierre Gönczy, Joseph Schmidt, Simon Lindhoud, Yehlin Cho, Casper A. Goverde, Brahm J. Yachnin, Bruno E. Correia, Srajan Kapoor, Christian Schellhaas, Sandrine Georgeon, Alex J. Vecchio, Jagrity Choudhury, Ana Alcaraz‐Serna, Martin Pačesa, Sergey Ovchinnikov, Lucas Kissling, Georgios N. Hatzopoulos, Daan C. Swarts, Patrick Barendse, Kourosh H. Ghamary, Laura Vinué, Ekaterina Pyatova
article en
98 citations

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. <sup>1</sup>) 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.

NatureVol. 646(8084)
SIB Swiss Institute of Bioinformatics (CH), University of Zurich (CH), Visterra (United States) (US), IIT@MIT (US), École Polytechnique Fédérale de Lausanne (CH), University at Buffalo, State University of New York (US), Massachusetts Institute of Technology (US), Wageningen University & Research (NL), University of Lausanne (CH)
Zero hunger
Openalex Percentile: Top 0%
Monoclonal and Polyclonal Antibodies Research
133.30
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