Computational Insight into the Mechanism of Serine Residue Racemization

Despite the known racemization of serine (Ser) residues in proteins from aged or diseased human brains, the mechanism of Ser racemization in peptides and proteins has not been studied. This is in contrast to the case of the rapid racemization of aspartic acid (Asp) residues, for which a succinimide-mediated mechanism is established. In a possible mechanism for Ser racemization, the enolization involving the H(alpha)-atom and the CO(alpha) group occurs by active participation of two H(2)O molecules. In this study, we computationally modeled this two-H(2)O mechanism of enolization for Ser and alanine (Ala) residues using model compounds, and the results were compared with each other and with the case of succinimide analogues reported in a separated paper. Our results suggest that Ser residues are much more racemization-prone than Ala residues, but to a lesser extent than Asp residues. The side-chain C-O bond of the Ser residue stabilizes the enolization transition state hyperconjugatively.