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

ABSTRACT: In proteins and peptides, d-aspartic acid (d-Asp) and d-?-Asp residues can be spontaneously formed via racemization of the succinimide intermediate formed from l-Asp and l-asparagine (l-Asn) residues. These biologically uncommon amino acid residues are known to have relevance to aging and pathologies. Although nonenzymatic, the succinimide racemization will not occur without a catalyst at room or biological temperature. In the present study, we computationally investigated the mechanism of succinimide racemization catalyzed by dihydrogen phosphate ion, H?PO?^-, by B3LYP/6-31+G(d,p) density functional theory calculations, using a model compound in which an aminosuccinyl (Asu) residue is capped with acetyl (Ace) and NCH? (Nme) groups on the N- and C-termini, respectively (Ace-Asu-Nme). It was shown that an H?PO?^- ion can catalyze the enolization of the H_?-C_?-C=O portion of the Asu residue by acting as a proton-transfer mediator. The resulting complex between the enol form and H?PO?^- corresponds to a very flat intermediate region on the potential energy surface lying between the initial reactant complex and its mirror-image geometry. The calculated activation barrier (18.8 kcal·mol^-1 after corrections for the zero-point energy and the Gibbs energy of hydration) for the enolization was consistent with the experimental activation energies of Asp racemization.

SUBMITTER: Takahashi O 

PROVIDER: S-EPMC5085730 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature