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

摘要

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_3C-NH-C(=O)-CH_2-CH_2-COOH and (H_2O)_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_3O~+ 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.