Modélisation de la reconnaissance et de la catalyse enzymatiques : Développements méthodologiques et détermination du mécanisme des Métionine Sulfoxyde Réductases de classe A

Abstract : The modeling of enzymatic recognition and catalysis has been examined in this work. In the first part, a docking software (AlgoGen-DivCon) to determine the optimal structure of a protein-ligand system, has been developed. The molecular system has been described using a semiempirical method combined with a linear scaling algorithm (Divide & Conquer), while the conformational search has been performed by a genetic algorithm (AlgoGen). Tests on different systems, including enzyme-substrate complexes, have been conducted to validate the approach. The second part concerns the study of the mechanism (reductase phase) of class A methionine sulfoxide reductases (MsrA), which catalyzes the reduction of oxidized methionine residues (MetSO). By means of molecular dynamics for different protonation states of the enzyme active site, we have shown that the substrate docking is particulary favourable for a Glu94H and Cys51- protonation state. The quantum chemistry study of the reduction mechanism, starting from the Michaelis complex, indicates that the process is initiated by the formation of a "sulfurane" species, after protonation of the sulfoxide and simultaneous formation of a S-S bond with Cys51. A second proton transfer from Tyr134 (or Tyr82) to the sulfurane OH group induces the formation of a water molecule and the dissociation of the S-O bond. The resulting sulfuranyl ion is finally hydrolyzed to form a sulfenic acid intermediate and the reduced substrate. According to the energy profile, this path could be simply described as a concerted and asynchronous mechanism involving two proton transfers.
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Eddy Thiriot. Modélisation de la reconnaissance et de la catalyse enzymatiques : Développements méthodologiques et détermination du mécanisme des Métionine Sulfoxyde Réductases de classe A. Autre. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10053⟩. ⟨tel-01748459⟩

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