One-shot design of functional protein binders with BindCraft
Martin Pacesa1, Lennart Nickel2,3, Christian Schellhaas2,3
1Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland. martin.pacesa@epfl.ch.
Nature
|August 27, 2025
Summary
BindCraft, an automated pipeline, designs novel protein binders with high success rates using AlphaFold2. This computational design approach shows therapeutic potential in allergy, gene editing, and targeted gene delivery.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Protein-protein interactions are fundamental to biological processes but challenging to design due to complex structural determinants.
- Current methods for designing protein binders often require extensive screening and optimization.
Purpose of the Study:
- To present BindCraft, an automated pipeline for de novo protein binder design.
- To demonstrate the efficacy of BindCraft in generating high-affinity binders for diverse and challenging targets.
Main Methods:
- Utilizing AlphaFold2 weights for de novo binder generation.
- Developing an automated pipeline for computational protein design.
- Validating designed binders against various targets, including cell-surface receptors and CRISPR-Cas9.
Main Results:
- Achieved experimental success rates of 10-100% for designed binders.
- Generated binders with nanomolar affinity without high-throughput screening.
- Demonstrated functional applications, including reducing allergen binding, modulating gene editing, and targeted gene delivery.
Conclusions:
- BindCraft offers a powerful and efficient approach to de novo protein binder design.
- The pipeline has broad applicability in therapeutics, diagnostics, and biotechnology.
- This work advances the 'one design-one binder' paradigm in computational protein engineering.
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