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Los modos de doble unión de la superficie de las protofibrillas del rojo del Congo al amiloide observados en
Chun Wu1, Zhixiang Wang, Hongxing Lei
1UC Davis Genome Center and Department of Applied Science, University of California, Davis, California 95616, USA.
Journal of the American Chemical Society
|February 1, 2007
Resumen
El rojo del Congo se une a las fibrillas amiloides en dos modos específicos, ofreciendo información sobre sus mecanismos inhibidores. Este descubrimiento podría conducir a nuevos medicamentos no peptídicos dirigidos a las enfermedades amiloides.
Área de la Ciencia:
- La biofísica es la biofísica.
- Biología Molecular Biología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- El rojo del Congo es una mancha establecida desde hace mucho tiempo para las fibrillas amiloides en los tejidos.
- Muestra débiles efectos inhibidores sobre la formación de fibrillas de beta amiloide y la toxicidad.
- La especificidad de unión precisa y los mecanismos de inhibición del rojo del Congo no se comprenden completamente.
Objetivo del estudio:
- Para caracterizar los modos específicos de unión de las protofibrillas rojas del Congo a las amiloides.
- Para dilucidar los mecanismos moleculares subyacentes a la acción inhibidora del rojo del Congo.
- Explorar el potencial para desarrollar nuevos inhibidores específicos del amiloide.
Principales métodos:
- Se emplearon simulaciones de dinámica molecular de todos los átomos con modelos de disolventes explícitos.
- Las simulaciones se centraron en una protofibrilla formada por el fragmento Sup35 de la proteína priónica de levadura (GNNQQNY).
- Mecánica molecular generalizada La superficie de nacimiento (MM-GBSA) se utilizó para la estimación de la energía de unión.
Principales resultados:
- Se identificaron dos modos de unión distintos del rojo del Congo a la protofibrilla GNNQQNY.
- El modo de unión primario, que implica ranuras a lo largo de las extensiones de la hoja beta, fue más estable (-5,7 kcal / mol) que el modo secundario.
- Se descubrió que las interacciones hidrofóbicas son cruciales para la afinidad de unión del rojo del Congo.
Conclusiones:
- Los modos de unión identificados, particularmente el primario, sugieren un mecanismo de reconocimiento general para las fibrillas amiloides por el rojo del Congo y moléculas similares.
- El modo de unión primaria ofrece mecanismos potenciales para interrumpir el apilamiento de hojas beta.
- Estos hallazgos allanan el camino para diseñar nuevos inhibidores no peptídicos para enfermedades relacionadas con la amiloide.
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