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Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
Published on: January 16, 2016
Las contribuciones de la compresión conformacional y la estabilización del estado de transición preferencial a la
Cristiano Ruch Werneck Guimarães1, Matthew P Repasky, Jayaraman Chandrasekhar
1Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, USA.
Journal of the American Chemical Society
|June 5, 2003
Resumen
La chorismato mutasa (CM) acelera las reacciones comprimiendo las conformaciones de ataque cercano (NAC) de su sustrato, en lugar de preorganizarlo. Esta compresión catalizada por enzimas está controlada entálpicamente, lo que explica la mejora significativa de la velocidad observada en la catálisis enzimática.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- La cinética de las enzimas.
- Química computacional es la química computacional.
Sus antecedentes:
- La chorismato mutasa (CM) cataliza un crucial reordenamiento de Claisen.
- La comprensión de la mejora de la velocidad catalizada por enzimas es clave para los estudios de mecanismos enzimáticos.
Objetivo del estudio:
- Para investigar el papel de las conformaciones cercanas al ataque (NAC) en las reacciones catalizadas por la corismato mutasa (CM).
- Para aclarar los mecanismos detrás de la mejora de la tasa proporcionada por CM.
Principales métodos:
- Simulaciones combinadas de mecánica cuántica y mecánica molecular (QM/MM).
- Cálculos de la perturbación de Montecarlo/energía libre (MC/FEP).
- Análisis de las preferencias conformacionales del sustrato en solución y sitio activo.
Principales resultados:
- El corismato existe predominantemente en las estructuras de NAC tanto en el agua (82%) como en el sitio activo de CM (100%).
- La preorganización enzimática en NACs no contribuye a la activación de la energía libre.
- La mejora de la tasa se debe principalmente a la compresión conformacional de los NAC por la enzima, un proceso controlado entálpicamente.
Conclusiones:
- El mecanismo catalítico primario de la CM implica la compresión conformacional impulsada entálpicamente de las conformaciones cercanas al ataque.
- La estabilización preferencial del estado de transición juega un papel secundario en la catálisis de CM.
- Los métodos computacionales reproducen con precisión las observaciones experimentales de la actividad enzimática.
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