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

Abstract

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 deltaH degrees and deltaS degrees 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.

Racemization of the Succinimide Intermediate Formed in Proteins and Peptides: A Computational Study of the Mechanism Catalyzed by Dihydrogen Phosphate Ion

“…Although the above succinimide-linked reactions in proteins and peptides are nonenzymatic, they will not occur at room or biological temperature without a catalyst because of high activation barriers [43,44,45,46,47,48,49]. Although buffer species are possible catalysts, we have little systematic insight into their possible catalytic roles.…”

Acetic Acid Can Catalyze Succinimide Formation from Aspartic Acid Residues by a Concerted Bond Reorganization Mechanism: A Computational Study

“…Succinimide formation has been regarded as a nucleophilic substitution at the carbonyl carbon comprised of two steps (an addition-elimination or a cyclization-dehydration mechanism) ( Scheme 2 ) [ 18 , 19 , 20 ]. The first step is an intramolecular addition (cyclization) in which the amide nitrogen of the C -terminal peptide bond nucleophilically attacks the carboxyl carbon of the Asp side chain.…”

“…The first step is an intramolecular addition (cyclization) in which the amide nitrogen of the C -terminal peptide bond nucleophilically attacks the carboxyl carbon of the Asp side chain. This gives a tetrahedral intermediate, which is probably a gem -diol at neutral to acidic pH [ 20 , 21 ]. In the second step, a water molecule is eliminated from the gem -diol group.…”

“…In the second step, a water molecule is eliminated from the gem -diol group. Both steps are thought to require a catalyst, because density-functional quantum-chemical calculations show that the energy barriers are too high without a catalyst [ 20 , 21 ]. Water is a good candidate as a catalyst of the succinimide-forming reactions, as we have recently shown computationally [ 22 , 23 , 24 ].…”

N-Chlorination rate of five-membered heterocyclic nitrogen compounds

“…In the literature, we have found information about the behaviour of aqueous solutions of SI in alkaline medium. It reveals the existence of a hydrolysis process of the SI with irreversible ring‐cleavage and formation of succinamic acid . The hydrolysis process is delayed until the pH values is above the p K a of succinimide .…”