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La entropía de configuración y la cooperatividad entre la unión de ligandos y la dimerización en los antibióticos
Sutjano Jusuf1, Patrick J Loll, Paul H Axelsen
1Department of Pharmacology, University of Pennsylvania, Philadelphia 19104, USA.
Journal of the American Chemical Society
|March 27, 2003
Resumen
Los antibióticos glicopéptidos muestran cooperatividad sin cambios estructurales. La unión de ligandos y la dimerización son cooperativas debido a la reducción de los costos entrópicos, impulsados por una actividad vibratoria alterada, no por cambios estructurales.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- La biofísica molecular es la biofísica molecular.
- Biología Química Biología química.
Sus antecedentes:
- La oligomerización y la unión de ligandos a menudo son cooperativas, generalmente impulsadas por cambios estructurales.
- Los antibióticos glicopéptidos muestran unión cooperativa sin alteraciones estructurales significativas, lo que plantea una cuestión mecanicista.
Objetivo del estudio:
- Investigar el mecanismo de cooperatividad en los antibióticos glicopéptidos en ausencia de cambios estructurales importantes.
- Para determinar si la dinámica vibratoria alterada puede explicar la cooperatividad observada.
Principales métodos:
- Simulaciones de dinámica molecular completamente solvatadas de cloroeremomicina, vancomicina y dechlorovancomicina.
- Análisis de modo normal casi armónico para derivar entropias de configuración.
- Análisis de las formas monoméricas y diméricas libres de ligandos y ligados a ligandos.
Principales resultados:
- Tanto la unión de ligandos como la dimerización incurren en un costo entrópico, indicado por los cambios a frecuencias más altas y amplitudes más bajas en los modos vibratorios.
- El costo entrópico combinado de la unión del ligando y la dimerización es menor que la suma de sus costos individuales.
- Las reducciones en la entropía configuracional explican suficientemente la cooperatividad experimentalmente observada.
Conclusiones:
- La cooperatividad bioquímica puede ser mediada por cambios en la actividad vibratoria, independientemente de cambios estructurales significativos.
- Este mecanismo de dinámica vibratoria alterada puede representar un principio alostérico general en diversos sistemas macromoleculares.
- La cooperatividad en los antibióticos glicopéptidos surge de ahorros entrópicos en los modos vibratorios en lugar de cambios conformacionales.
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