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Mecanismo de unión al sustrato de la proteasa del VIH-1 a partir de simulaciones atomistas de disolvente explícito y
Fabio Pietrucci1, Fabrizio Marinelli, Paolo Carloni
1International School for Advanced Studies (SISSA-ISAS), via Beirut 2-4, I-34014 Trieste, Italy.
Journal of the American Chemical Society
|August 4, 2009
Resumen
Este estudio revela cómo un sustrato peptídico se une a la proteasa VIH-1 de tipo salvaje utilizando dinámicas moleculares. Los hallazgos sugieren que las mutaciones pueden afectar la unión de manera diferente para los sustratos naturales frente a los peptidomiméticos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Química computacional es la química computacional.
Sus antecedentes:
- Comprender la función de la proteasa del VIH-1 es crucial para el desarrollo de terapias antivirales.
- El mecanismo de unión de los sustratos a la proteasa del VIH-1 influye en la eficacia del fármaco.
Objetivo del estudio:
- Para dilucidar el mecanismo de unión de un sustrato peptídico específico a la proteasa VIH-1 de tipo salvaje.
- Para investigar la vía de unión y la energía utilizando técnicas avanzadas de simulación.
Principales métodos:
- Simulaciones sesgadas de dinámica molecular de todos los átomos (1.6 micros) en agua explícita.
- Técnica de metadinámica de intercambio de sesgo para explorar el espacio de configuración mediante el sesgo de siete coordenadas de reacción.
- Cálculo de la energía libre de unión y las constantes cinéticas para la asociación y la disociación.
Principales resultados:
- La estructura del complejo de Michaelis se obtuvo con alta precisión (rmsd de la columna vertebral de 0,9 A).
- La energía libre de enlace calculada (-6 kcal/mol) y las constantes cinéticas (1.3 x 10^6 M^-1 s^-1 asociación, 57 s^-1 disociación) se alinean con los datos experimentales.
- La vía de unión primaria implica que el sustrato se deslice a través de un canal lateral sin una abertura significativa del colgajo.
Conclusiones:
- El mecanismo de unión observado difiere de la unión esperada al sustrato de poliproteína natural, que probablemente implica la apertura de la aleta.
- Esta distinción sugiere que las mutaciones en la proteasa del VIH-1 podrían afectar diferencialmente la cinética de unión de los fármacos peptidomiméticos y sustratos naturales.
- Los hallazgos proporcionan información sobre la especificidad del sustrato y los posibles mecanismos de resistencia a los medicamentos.
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