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Molecules 2016, 21(3), 327; doi:10.3390/molecules21030327

A Computational Study of the Mechanism of Succinimide Formation in the Asn–His Sequence: Intramolecular Catalysis by the His Side Chain

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
These authors contributed equally to this work.
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Academic Editors: Jose M. Palomo and Chris Frost
Received: 30 January 2016 / Revised: 3 March 2016 / Accepted: 4 March 2016 / Published: 9 March 2016
(This article belongs to the Special Issue Biomolecules Modification)
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Abstract

The rates of deamidation reactions of asparagine (Asn) residues which occur spontaneously and nonenzymatically in peptides and proteins via the succinimide intermediate are known to be strongly dependent on the nature of the following residue on the carboxyl side (Xxx). The formation of the succinimide intermediate is by far the fastest when Xxx is glycine (Gly), the smallest amino acid residue, while extremely slow when Xxx is bulky such as isoleucine (Ile) and valine (Val). In this respect, it is very interesting to note that the succinimide formation is definitely accelerated when Xxx is histidine (His) despite its large size. In this paper, we computationally show that, in an Asn–His sequence, the His side-chain imidazole group (in the neutral Nε-protonated form) can specifically catalyze the formation of the tetrahedral intermediate in the succinimide formation by mediating a proton transfer. The calculations were performed for Ace−Asn−His−Nme (Ace = acetyl, Nme = methylamino) as a model compound by the density functional theory with the B3LYP functional and the 6-31+G(d,p) basis set. We also show that the tetrahedral intermediate, once protonated at the NH2 group, easily releases an ammonia molecule to give the succinimide species. View Full-Text
Keywords: asparagine residue; deamidation; succinimide; nonenzymatic reaction; Asn–His sequence; intramolecular catalysis; histidine imidazole group; proton-transfer mediator; computational chemistry; density functional theory asparagine residue; deamidation; succinimide; nonenzymatic reaction; Asn–His sequence; intramolecular catalysis; histidine imidazole group; proton-transfer mediator; computational chemistry; density functional theory
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Takahashi, O.; Manabe, N.; Kirikoshi, R. A Computational Study of the Mechanism of Succinimide Formation in the Asn–His Sequence: Intramolecular Catalysis by the His Side Chain. Molecules 2016, 21, 327.

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