Estudio de interacciones de glicosiltransferasas mediante simulaciones de dinámica molecular

Montesa Gómez, Alejandro
Merino Filella, Pedro (dir.)

Universidad de Zaragoza, CIEN, 2024
Departamento de Química Orgánica,

Máster Universitario en Biofísica y Biotecnología Cuantitativa / Master in Biophysics and Quantitative Biotechnology

Resumen: Fringe proteins are GT-A inverting glycosyltransferases that catalyze the addition of GlcNAc (donor) to O-fucosylated EGF motifs of Notch receptors (acceptor), modifying its ligand-binding affinity. In this study, molecular dynamics simulations of the mouse homolog, Mfng, in different states of its proposed catalytic cycle, have been performed to obtain deeper insights of its interactions and mechanism. Simulations of UDP and UDP-GlcNAc bound systems revealed how these molecules interact with Fringe’s active site and coordinate the Mn2+ metal ion, necessary for the protein catalytic activity. Interesting results have been obtained for ternary systems (protein-donor-acceptor), where changes in the secondary structure of a long, flexible loop, which was modelled after crystallization, demonstrate Fringe’s activation upon substrate binding, similarly to other GT-A fold glycosyltransferases. These studies establish coherent starting points for more advanced mechanistic studies, for which it is necessary to use QM/MM or metadynamics approaches that will allow the complete elucidation of the reaction mechanism.

Tipo de Trabajo Académico: Trabajo Fin de Master