Modelling the hydrolysis of succinimide: Formation of aspartate and reversible isomerization of aspartic acid via succinimide

In the present study, we have modelled the nucleophilic attack of water and a hydroxyl anion on the carbonyl carbon of a succinimide derivative leading to aspartate and aspartic acid. Calculations have been carried out at the B3LYP/ 6-31+G* level in a vacuum. The IEF-PCM methodology has been used to carry out single point calculations in solution. In neutral medium, hydrolysis is facilitated by the presence of a polar continuum, whereas in basic medium the polar environment hinders the hydrolysis of succinimide. The ΔH° and ΔS° values for the cyclization reactions of aspartic acid yielding succinimide are 29.2 kJ mol^-1 and 133.5 kJ mol^-1 K^-1 respectively in accordance with the experimental results on the isomerization of the Ac-Asp-Gly-NHMe dipeptide unit. In a neutral medium, the isoaspartate : aspartate is found to be 2.2 : 1 in a vacuum and 3.4 : 1 in solution, in line with the experimental findings based on the hydrolysis of a tetrapeptide (Ac-Gly-Asn-Gly-Gly-NHMe) and a hexapeptide (Val-Tyr-Pro-Asn-Gly-Ala) where this ratio was found to be 3.1 : 1.