Accelerated Racemization of Aspartic Acid and Asparagine Residues via Succinimide Intermediates: An ab Initio Theoretical Exploration of Mechanism

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• 作者：Jennifer L. Radkiewicz ; H. Zipse ; Steven Clarke ; and K. N. Houk
• 刊名：Journal of the American Chemical Society
• 出版年：1996
• 出版时间：September 25, 1996
• 年：1996
• 卷：118
• 期：38
• 页码：9148 - 9155
• 全文大小：309K
• 年卷期：v.118,no.38(September 25, 1996)
• ISSN：1520-5126

文摘

Aspartic acid and asparagine residues racemize rapidlyrelative to other amino acid residues in proteinsand peptides. This has been attributed to the increased acidity ofthe -carbons of succinimide residues derivedfrom the spontaneous cyclizations of these residues. To understandthe basis of this effect, the acidities of modelcompounds were calculated using ab initio quantum mechanics(RHF/6-31+G*). The results were also checkedwith DFT (Becke3LYP/6-31+G*) and solvent cavity models (IPCM andSCIPCM). The geometries of succinimide,2-pyrrolidinone, and the derived enolate anions were optimized, and thegas phase deprotonation energies werecalculated. The imide is more acidic than the amide by 18 kcal/molin the gas phase. Since there is a qualitativecorrelation between gas phase and aqueous acidities, this resultprovides an explanation for the experimentalobservations that the rate of peptidyl succinimide racemization can be~10⁵ times greater than that of unmodifiedaspartic acid residues. To quantitate the source of thesuccinimide acidity, the geometries and CH acidities ofvariousconformations of N-formylacetamide and acetamide, acyclicmodels of succinimide and 2-pyrrolidinone, and3-oxobutanal and acetone, acyclic models lacking the nitrogen atom,were studied. The importance of resonanceeffects for increasing the acidity of the -carbon of succinimide wasestablished, but electrostatic and inductiveeffects also have an important influence on acidities. The acidityof succinimide is compared to the acidities ofseveral peptide models. Isosuccinimide, an alternative degradationproduct of aspartic acid and asparagine residues,is also be expected to be racemization prone by similarmechanisms.