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Los péptidos de lazo: explorando el paisaje plegable de los motivos entrelazados más pequeños de la naturaleza

Gabriel C A da Hora¹, Myongin Oh¹, Marcus C Mifflin¹

¹Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.

Journal of the American Chemical Society

|January 3, 2024

Resumen

Las simulaciones computacionales revelan que el plegamiento de péptidos de novo es raro. Sin embargo, la modificación de las secuencias y las condiciones de reacción pueden estabilizar las estructuras pre-lasso, ayudando al desarrollo terapéutico.

Área de la Ciencia:

Productos naturales Química
Biología computacional
La biofísica

Sus antecedentes:

Los péptidos de lazo son productos naturales con estructuras roscadas únicas.
Su pequeño tamaño y estabilidad ofrecen potencial terapéutico, pero la síntesis está limitada por la complejidad del plegado.
Comprender el plegamiento de novo es crucial para acceder a estas moléculas.

Objetivo del estudio:

Investigar la propensión al plegamiento del péptido láser antimicrobiano microcina J25 (MccJ25) mediante simulaciones.
Desarrollar algoritmos para distinguir entre precursores roscados y no roscados y determinar el uso manual.
Identificar estrategias para facilitar el plegado de péptidos de novo.

Principales métodos:

Se emplearon simulaciones de dinámica molecular para estudiar el plegamiento de MccJ25.
Se desarrollaron nuevos algoritmos para analizar las estructuras de péptidos y las vías de plegado.
Se exploraron las modificaciones de la secuencia, las funcionalidades no naturales y las condiciones de pH.

Principales resultados:

MccJ25 forma pre-lasos diestros, en contra de las predicciones anteriores.
La estructura pre-lasso nativa es metastable, favoreciendo los estados desplegados.
Las secuencias y condiciones modificadas (por ejemplo, la protonación de histidina) estabilizan significativamente las conformaciones pre-lasso.

Conclusiones:

El plegamiento de novo de los péptidos láser es generalmente raro debido a la inestabilidad inherente.
Los métodos computacionales son valiosos para caracterizar el plegamiento de péptidos láser.
La optimización de la secuencia, el empleo de modificaciones no naturales y el control de las condiciones de reacción pueden facilitar la formación de estructuras de lazo para aplicaciones terapéuticas.

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