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Detection of Detergent-sensitive Interactions Between Membrane Proteins
Published on: March 7, 2018
Las interacciones de Van der Waals dominan la asociación ligando-proteína en un sitio de unión a la proteína ocluido
Elizabeth Barratt1, Richard J Bingham, Daniel J Warner
1Astbury Centre for Structural Molecular Biology, School of Biochemistry & Microbiology, University of Leeds, Leeds LS2 9JT, UK.
Journal of the American Chemical Society
|August 18, 2005
Resumen
La unión de 2-metoxi-3-isobutilpirazina (IBMP) a la proteína urinaria mayor del ratón (MUP) es impulsada por la entalpía, no por la entropía. Esta termodinámica de unión inusual se atribuye a las interacciones de dispersión favorables en el bolsillo de unión mal solvado.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Química Física es la química física.
Sus antecedentes:
- Las principales proteínas urinarias (MUP) son lipocalinas involucradas en la unión y el transporte de feromonas.
- El bolsillo de unión de MUP-1 es altamente hidrofóbico, lo que sugiere típicamente una unión de ligandos impulsada por la entropía.
- La 2-metoxi-3-isobutilpirazina (IBMP) es un compuesto aromático volátil que se encuentra en varios sistemas biológicos.
Objetivo del estudio:
- Para dilucidar las fuerzas motrices termodinámicas detrás de la unión de IBMP al MUP del ratón.
- Investigar el papel de la solvación y los cambios en la estructura de las proteínas en el proceso de unión.
- Caracterizar las interacciones específicas que rigen la formación del complejo IBMP-MUP.
Principales métodos:
- Calorimetría de titulación isotérmica (ITC) para la termodinámica global.
- Espectroscopia de RMN y cristalografía de rayos X para obtener información estructural.
- Simulaciones de dinámica molecular de todos los átomos y mutagenesis dirigida al sitio (Y120F) para sondear interacciones y solvación.
Principales resultados:
- La unión de IBMP a MUP está dominada por una entalpía favorable, en contraste con la unión hidrofóbica típica.
- Existe un único enlace de hidrógeno entre Tyr120 e IBMP en la proteína de tipo salvaje.
- La mutagenesis (Y120F) y las simulaciones indican que la solvación y el "apretamiento" de las proteínas no son los principales contribuyentes a la entalpía de unión.
- Las interacciones de dispersión favorables en un bolsillo mal solvado impulsan la termodinámica de enlace.
Conclusiones:
- La unión de IBMP a MUP es un proceso impulsado entálpicamente.
- Las interacciones de dispersión, facilitadas por una mala disolución de la bolsa de unión, son los principales contribuyentes a la entalpía de unión.
- Este estudio revela una firma termodinámica no clásica para la unión de ligandos en bolsas de proteínas hidrofóbicas.
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