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La mecánica funcional evolucionariamente conservada a través de las proteasas asparticas similares a la pepsina y
Michele Cascella1, Cristian Micheletti, Ursula Rothlisberger
1International School for Advanced Studies, INFM-DEMOCRITOS Modeling Center for Research in Atomistic Simulation, Via Beirut 2-4, 34014 Trieste, Italy.
Journal of the American Chemical Society
|March 18, 2005
Resumen
Las proteasas aspárticas, como la proteasa del VIH-1, utilizan la flexibilidad conformacional para la función. Los residuos conservados modulan la actividad enzimática a través de movimientos a gran escala, un mecanismo común en todas las familias de proteasas asparticas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Enzimología Enzimología.
Sus antecedentes:
- La función de la proteasa aspartica del VIH-1 está vinculada a su flexibilidad estructural.
- Las proteasas asparticas parecidas a la pepsina comparten características estructurales conservadas.
Objetivo del estudio:
- Investigar si la flexibilidad conformacional influye en la función de las proteasas asparticas similares a la pepsina.
- Para identificar los residuos conservados y su papel en la actividad enzimática.
Principales métodos:
- Alineación de secuencias para identificar residuos conservados.
- Simulaciones clásicas de dinámica molecular (DM). simulaciones.
- Cálculos de energía libre.
- Análisis funcional de energía basado en topología.
Principales resultados:
- Los residuos conservados se agrupan en tres regiones clave: cerca del sitio activo, hojas beta y un área expuesta a disolventes.
- Las regiones conservadas, a pesar de su baja movilidad, impulsan movimientos de proteínas a gran escala que influyen en la distancia entre el sustrato y el aspartato catalítico.
- La energía libre de la activación enzimática se ve significativamente afectada por estos movimientos a gran escala.
- Existe un mecanismo común de modulación de la actividad enzimática en las proteasas asparticas eucariotas y retrovirales.
Conclusiones:
- Las proteasas asparticas emplean un mecanismo conservado de flexibilidad conformacional para modular la actividad enzimática.
- La evolución ha seleccionado movimientos funcionales similares en las proteasas asparticas, a pesar de las variaciones en sus pliegues.
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