Intramolecular cyclization of aspartic acid residues assisted by three water molecules: a density functional theory study

This is the authors' abstract. We don't add key points for this paper.

Aspartic acid (Asp) residues in peptides and proteins ( l -Asp) are known to undergo spontaneous nonenzymatic reactions to form l - β -Asp, d -Asp, and d - β -Asp residues. The formation of these abnormal Asp residues in proteins may affect their three-dimensional structures and hence their properties and functions. Indeed, the reactions have been thought to contribute to aging and pathologies. Most of the above reactions of the l -Asp residues proceed via a cyclic succinimide intermediate. In this paper, a novel three-water-assisted mechanism is proposed for cyclization of an Asp residue (forming a gem -diol precursor of the succinimide) by the B3LYP/6-31 + G(d,p) density functional theory calculations carried out for an Asp-containing model compound (Ace−Asp−Nme, where Ace = acetyl and Nme = NHCH 3 ). The three water molecules act as catalysts by mediating 'long-range' proton transfers. In the proposed mechanism, the amide group on the C-terminal side of the Asp residue is first converted to the tautomeric iminol form (iminolization). Then, reorientation of a water molecule and a conformational change occur successively, followed by the nucleophilic attack of the iminol nitrogen on the carboxyl carbon of the Asp side chain to form the gem -diol species. A satisfactory agreement was obtained between the calculated and experimental energetics.