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Modelling the active site of glyceraldehyde-3 phosphate dehydrogenase with the LSCF formalism

Abstract : In the framework of a theoretical approach to the relationship between structure and reactivity of the catalytic centers of enzymes, glyceraldehyde-3 phosphate dehydrogenase (GAPDH) has been chosen as a model enzyme. In GAPDH, the proximity of His 176 increases the reactivity of Cys 149 at neutral pH; however, its presence alone is not sucient to explain the reactivity of the catalytic Cys. In order to determine which other interactions play an important role, a study of the geometric and electronic structure of the catalytic site has been made using a hybrid quantum mechanics/ molecular mechanics local self-consistent ®eld method. This allows the computation of the electronic properties of amino acid residues in subsystems in¯uenced by other parts of the macromolecule. The quantum subsystem was centered on the Cys 149 residue of GAPDH. The structures of GAPDH taken from the crystallographic database did not include hydrogen atoms and these had to be added taking into account the fact that, in the active site, His 176 has three tautomeric forms: d-His protonated,-His protonated and His ‡. The results presented here suggest that the most stable HisF F FCys system in GAP-DH is a strongly hydrogen-bonded Cys À 149 aHis ‡ 176 ion pair.
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Alain Cartier, David Brown, Bernard Maigret, Sandrine Boschi-Muller, Sophie Rahuel-Clermont, et al.. Modelling the active site of glyceraldehyde-3 phosphate dehydrogenase with the LSCF formalism. Theoretical Chemistry Accounts: Theory, Computation, and Modeling, Springer Verlag, 1999, 101 (1-3), pp.241 - 245. ⟨10.1007/s002140050436⟩. ⟨hal-01682230⟩



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