Computational Studies on Water-Catalyzed Mechanisms for Stereoinversion of Glutarimide Intermediates Formed from Glutamic Acid Residues in Aqueous Phase.

Tomoki Nakayoshi,Shuichi Fukuyoshi,Koichi Kato,Akifumi Oda,Eiji Kurimoto

doi:10.3390/ijms20102410

Abstract

Aspartic acid (Asp) residues are prone to non-enzymatic stereoinversion, and Asp-residue stereoinversion is believed to be mediated via a succinimide (SI) intermediate. The stereoinverted Asp residues are believed to cause several age-related diseases. However, in peptides and proteins, few studies have reported the stereoinversion of glutamic acid (Glu) residues whose structures are similar to that of Asp. We previously presumed that Glu-residue stereoinversion proceeds via a glutarimide (GI) intermediate and showed that the calculated activation barriers of SI- and GI-intermediate stereoinversion are almost equivalent in the gas phase. In this study, we investigated the stereoinversion pathways of the l-GI intermediate in the aqueous phase using B3LYP density functional methods. The calculated activation barrier of l-GI-intermediate stereoinversion in the aqueous phase was approximately 36 kcal·mol−1, which was much higher than that in the gas phase. Additionally, as this activation barrier exceeded that of Asp-residue stereoinversion, it is presumed that Glu-residue stereoinversion has a lower probability of proceeding under physiological conditions than Asp-residue stereoinversion.

Highlights

Proteins comprise approximately 20 amino acids, which, except for glycine, have asymmetric carbon atoms
The energy minima and transition the model and employing we investigated theAlltwo-water-catalyzed stereoinversion geometries were corrected for the zero-point energies (ZPEs) obtained by vibrational frequency state (TS) geometries were optimized without anyemploying constraintsthe by polarizablemodel continuum model (PCM)
Enolization proceeded via one step, and two water molecules placed around the capped l-GI residue acted as catalysts

Summary

Introduction

Proteins comprise approximately 20 amino acids, which, except for glycine, have asymmetric carbon atoms. D-amino acid residues have been detected in biological proteins in various aging tissues, e.g., crystallin in the lens [9,10,11,12], amyloid β in the brain [5,8,13], and elastin in the aorta, ligaments, and skin [14,15,16]. As these proteins are biosynthesized from only l-amino acids, d-amino acid residues identified in aging proteins are assumed to be formed by the stereoinversion of l-amino acid residues. The formation of d-amino acid residues dramatically affects the surrounding environment and the stereoinversion of certain amino acid residues produces significant conformational changes in the entire protein [17,18,19].

Methods

Discussion

Conclusion