Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5417479 | Journal of Molecular Structure: THEOCHEM | 2009 | 8 Pages |
Abstract
We have studied the initial stages of hydrolysis in the monomeric aspartic proteinases by performing ab initio calculations (Hartree-Fock, MP2, DFT) on the active site of endothiapepsin. The crystallographic coordinates of a difluorostatone inhibitor complexed with endothiapepsin were used to generate a template for the initial enzyme/substrate complex. The active site was modelled as a formic acid-formate anion moiety (representing the catalytic aspartates, Asp-32 and Asp-215) and a bound water molecule. Acetamide was used to represent the substrate, and residues Gly-34, Ser-35, Gly-217, and Thr-218, which all interact with the active site, were modelled using formamide and methanol. The calculations predict that T218 plays a direct role in catalysis by forming a strong hydrogen bond with the water oxygen during the initial stages of nucleophilic attack. S35 plays an indirect role by lowering the pKa of Asp-32 and facilitating the formation of the gem-diol intermediate. The predicted reaction pathway is unusual because it involves two local minima, with very short Owater...Csubstrate distances, which are stabilised by T218.
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Authors
A.J. Beveridge,