How is the anionic tetrahedral intermediate involved in the isomerization of aspartyl peptides to iso-aspartyl ones? A DFT study on the tetra-peptide

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An isomerization reaction of a tetra-peptide, Ac-Gly-Asp-Gly-Gly-NHMe → Ac-Gly-isoAsp-Gly-Gly-NHMe, was investigated by DFT calculations. Thirteen water molecules were added to the peptide for simulating proton transfers during the isomerization. As a starting analysis, the number (m) of water molecules participating in ready proton transfers was examined by the use of a small model system, H(3)C-NH-C(=O)-CH(2)-CH(2)-COOH and (H(2)O)(m). The m = 2 stepwise path was found to be of the smallest activation free energy. On the basis of this result, the first isomerization path of the tetra-peptide was obtained with four elementary processes. The m = 2 proton-transfer pattern is involved in them. A different proton transfer gives the second isomerization path with six elementary processes. The second path (with ionization) is more likely than the first one (without ionization). Formation of the five membered rings of the aminosuccinimidyl-residue and anionic tetrahedral intermediates enhances the encapsulation of H(3)O(+) through the wound tetra-peptide ring. The role of the hydrogen bonds on the encapsulation was discussed in terms of the optimized geometries of proton-transfer transition states and intermediates.