Modeling the Reaction Coordinate of Beta-Galactocerebrosidase

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Modeling the Reaction Coordinate of Beta-Galactocerebrosidase

Alba Nin-Hill 1 , Lluis Raich 1 , Carme Rovira 1,2

1 Departament de Quimica Inorganica i Organica and Institut de Quimica Teorica i Computacional (IQTC). Universitat de Barcelona, Barcelona, Spain, 2 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain

Non-functional β-galactocerebrosidase (GALC), a family 59 glycoside hydrolase (GH), is responsible for Krabbe disease, a neurodegenerative disease that is still incurable. The first crystallographic structure of the Michaelis complex (MC) of GALC that was obtained [1] shows that the galactoside saccharide at the -1 subsite adopts an unusual chair conformation, whereas other β-GHs often feature distorted substrate conformations that are preactivated for catalysis [2]. However, the GALC structure was determined under non-reactive conditions (non-optimal pH), which could affect the conformation of the substrate. In this work, we address this issue by means of quantum mechanics/molecular mechanics (QM/MM) metadynamics methods [2,3], uncovering the substrate conformation along the reaction coordinate on GALC.

Reaction coordinate along the glycosylation step catalyzed by β-GALC departing from the ⁴C₁ and ¹S₃ MC conformations.

Hill CH.; Graham SC.; Read RJ.; Deane JE. Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease. PNAS 2013, 110(51), 20479-84.

Ardèvol A.; Rovira C. Reaction mechanisms in carbohydrate-active enzymes: glycoside hydrolases and glycosyltransferases. Insights from ab initio quantum mechanics/molecular mechanics dynamic simulations. JACS. 2015, 137(24), 7528-47.

Laio A.; Parrinello M. Escaping free-energy minima. PNAS 2002, 99.20, 12562-12566

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