Computational modeling of the enolization in a direct mechanism of racemization of the aspartic acid residue.
The rapid racemization of aspartic acid (Asp) residues in peptides and proteins is due mainly to the succinimide intermediate. However, there should be another mechanism for Asp racemization without intermediacy of the succinimide. The direct H-atom abstraction from the C(alpha)-atom that leads to the enol form of the Asp residue is one possibility. In another study, we have computationally predicted that the corresponding enolization in the succinimide intermediate occurs by assistance of two H(2)O molecules. In the present study, we, therefore, investigated the similar two-H(2)O-assisted enolization for an Asp-containing model compound by the same computational method as before (B3LYP/6-31+G**). Rather surprisingly, the activation barrier for the two-H(2)O-assisted enolization of the Asp residue (protonated form) was calculated to be almost equal to that for the corresponding succinimide. Therefore, an Asp residue is expected to be prone to enolization to almost the same degree as the corresponding succinimide form, and the 'direct' (i.e., non-succinimide-mediated) mechanism of Asp racemization may compete with the succinimide-mediated mechanism.
Takahashi
Ohgi
O
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. ohgi@tohoku-pharm.ac.jp
Kobayashi
Kana
K
Oda
Akifumi
A
D001224:Aspartic Acid / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D013237:Stereoisomerism; D013388:Succinimides / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D013388:Succinimides; D014867:Water; C032620:succinimide; D001224:Aspartic Acid