The conformational free-energy landscape of beta-D-mannopyranose: evidence for a S-1(5) -> B-2,B-5 -> S-O(2) catalytic itinerary in beta-mannosidases

Albert Ardèvol, Xevi Biarnés, Antoni Planas, Carme Rovira

Research output: Indexed journal article Articlepeer-review

43 Citations (Scopus)

Abstract

The mechanism of glycosidic bond cleavage by glycosidases involves substrate ring distortions in the Michaelis complex that favor catalysis. Retaining β-mannosidases bind the substrate in a 1S5 conformation, and recent experiments have proposed an unusual substrate conformational pathway (1S5 → B2,5OS2) for the hydrolysis reaction. By means of Car-Parrinello metadynamics simulations, we have obtained the conformational free-energy surface (FES) of a β-d-mannopyranose molecule associated with the ideal Stoddart conformational diagram. We have found that 1S 5 is among the most stable conformers and simultaneously is the most preactivated conformation in terms of elongation/shortening of the C1-O1/C1-O5 bonds, C1-O1 orientation, and charge development at the anomeric carbon. Analysis of the computed FES gives support to the proposed 1S 5 → B2,5OS2 catalytic itinerary, showing that the degree of preactivation of the substrate in glycoside hydrolases (GHs) is related to the properties of an isolated sugar ring. We introduce a simple preactivation index integrating several structural, electronic, and energetic properties that can be used to predict the conformation of the substrate in the Michaelis complex of any GH.

Original languageEnglish
Pages (from-to)16058-16065
Number of pages8
JournalJournal of the American Chemical Society
Volume132
Issue number45
DOIs
Publication statusPublished - 17 Nov 2010

Keywords

  • Molecular-dynamics
  • B3lyp/6-311++g-asterisk-asterisk level
  • Glycosidase mechanisms
  • Substrate distortion
  • Density functionals
  • Reaction coordinate
  • Transition-state
  • D-glucopyranose
  • Dft
  • Approximation

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