Computational studies on non-succinimide-mediated stereoinversion mechanism of aspartic acid residues assisted by phosphate

ABSTRACT

Although nearly all of the amino acids that constitute proteins are l-amino acids, d-amino acid residues in human proteins have been recently reported. d-amino acid residues cause a change in the three-dimensional structure of proteins, and d-aspartic acid (Asp) residues are considered to be one of the causes of age-related diseases. The stereoinversion of Asp residues in peptides and proteins is thought to proceed via a succinimide intermediate; however, it has been reported that stereoinversion can occur even under conditions where a succinimide intermediate cannot be formed. In order to elucidate the non-succinimide-mediated stereoinversion pathway, we investigated the stereoinversion of l-Asp to d-Asp catalysed by phosphate and estimated the activation barrier using B3LYP/6−31+G(d,p) density functional theory (DFT) calculations. For the DFT calculations, a model compound in which the Asp residue is capped with acetyl and methyl-amino groups on the N- and C-termini, respectively, was used. The calculated activation barrier was not excessively high for the stereoinversion to occur in vivo. Therefore, this stereoinversion mechanism may compete with the succinimide-mediated mechanism.

GRAPHICAL ABSTRACT

KEYWORDS:

• Aspartic acid residue
• stereoinversion
• non-enzymatic reaction
• phosphate-catalysed
• density functional theory

Acknowledgment

This work was supported by grants-in-aid for scientific research [grant number 15H01064], [grant number 17K08257], [grant number 26460034] from the Japan Society for the Promotion of Science. The authors would like to thank Enago (www.enago.jp) for the English language review.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Japan Society for the Promotion of Science [grant number 15H01064], [grant number 17K08257], [grant number 26460034].