Quantum Chemical Analysis of the Unfolding of a Penta-alanyl 3(10)-Helix Initiated by HO(center dot), HO(2)(center dot) and O(2)(-center dot)

TitleQuantum Chemical Analysis of the Unfolding of a Penta-alanyl 3(10)-Helix Initiated by HO(center dot), HO(2)(center dot) and O(2)(-center dot)
Publication TypeJournal Article
Year of Publication2011
AuthorsOwen MC, Viskolcz B, Csizmadia IG
JournalJournal Of Physical Chemistry B
Volume115
Pagination8014-8023
Date PublishedJUN 23
ISSN1520-6106
Abstract

In order to elucidate the mechanisms of radical-initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C(alpha), C(beta) and amide nitrogen of Ala(3) in a homopeptapeptide (N-Ac-AAAAA-NH(2); A5) by HO(center dot), HO(2)(center dot), and O(2)(-center dot) were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (Delta H degrees), Gibbs free energy (Delta G degrees), and entropy (Delta S degrees), of the reactants and products of these reactions were computed with A5 in the 3(10)-helical (A5(Hel)) and fully extended (A5(Ext)) conformations at the B3LYP/6-31G(d) and B3LYP/6-311+G(d,p) levels of theory, both in the gas phase and using the C-PCM implicit water model. With quantum chemical calculations, we have shown that H abstraction is the most favorable at the C(alpha) followed by the C(beta), then amide N in a model helix. The secondary structure has a strong influence on the bond dissociation energy of the H-C(alpha), but a negligible effect on the dissociation energy of the H-CH(2) and H-N bonds. The HO(center dot) radical is the strongest hydrogen abstractor, followed by HO(2)(center dot) and finally O(2)(-center dot). More importantly, secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by hindering the potential electron delocalization at the C(alpha) when the peptide is in the extended conformation. We also show that he unfolding of the A5 peptide radicals have a significantly higher propensity to unfold than the closed shell A5 peptide and confirm that only the HO(center dot) can initiate the unfolding of A5(Hel) and the formation of A5(Ext)(center dot). By comparing the structures, energies, and thermodynamic functions of A5 and its radical derivatives, we have shown how free radicals can initiate the unfolding of helical structures to beta-sheets in the cellular condition known as oxidative stress.

DOI10.1021/jp202345p