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Diseño de un solo disparo de los aglutinantes de proteínas funcionales con 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
Resumen
BindCraft, una tubería automatizada, diseña nuevos aglutinantes de proteínas con altas tasas de éxito utilizando AlphaFold2. Este enfoque de diseño computacional muestra potencial terapéutico en alergia, edición de genes y entrega de genes dirigidos.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Biología computacional
Sus antecedentes:
- Las interacciones proteína-proteína son fundamentales para los procesos biológicos, pero son difíciles de diseñar debido a determinantes estructurales complejos.
- Los métodos actuales para diseñar aglutinantes de proteínas a menudo requieren una selección y optimización extensas.
Objetivo del estudio:
- Para presentar BindCraft, una tubería automatizada para el diseño de aglutinantes de proteínas de novo.
- Demostrar la eficacia de BindCraft en la generación de aglutinantes de alta afinidad para objetivos diversos y desafiantes.
Principales métodos:
- Utilizando pesas AlphaFold2 para la generación de nuevo aglutinante.
- Desarrollo de una tubería automatizada para el diseño computacional de proteínas.
- Validación de enlaces diseñados contra varios objetivos, incluidos los receptores de superficie celular y CRISPR-Cas9.
Principales resultados:
- Se han logrado tasas de éxito experimentales del 10 al 100% para los aglutinantes diseñados.
- Enlaces generados con afinidad nanomolar sin cribado de alto rendimiento.
- Aplicaciones funcionales demostradas, incluida la reducción de la unión alérgica, la edición de genes modulados y la entrega de genes dirigidos.
Conclusiones:
- BindCraft ofrece un enfoque potente y eficiente para el diseño de aglutinantes de proteínas de novo.
- La tubería tiene una amplia aplicabilidad en terapia, diagnóstico y biotecnología.
- Este trabajo hace avanzar el paradigma de "un diseño-un conector" en la ingeniería computacional de proteínas.
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