Quantum chemical analysis of the unfolding of a penta-alanyl 3 10-helix initiated by HO·, HO2 · and O2

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In order to elucidate the mechanisms of radical-initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C α, Cβ, and amide nitrogen of Ala3 in a homopeptapeptide (N-Ac-AAAAA-NH2; A5) by HO·, HO2·, and O2 were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (ΔHo), Gibbs free energy (ΔG o), and entropy (ΔSo), of the reactants and products of these reactions were computed with A5 in the 310-helical (A5 Hel) and fully extended (A5Ext) 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 Cα, followed by the Cβ, then amide N in a model helix. The secondary structure has a strong influence on the bond dissociation energy of the H-Cα, but a negligible effect on the dissociation energy of the H-CH2 and H-N bonds. The HO· radical is the strongest hydrogen abstractor, followed by HO2· and finally O2. More importantly, secondary structure elements, such as H-bonds in the 310-helix, protect the peptide from radical attack by hindering the potential electron delocalization at the Cα 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· can initiate the unfolding of A5Hel and the formation of A5Ext·. 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 β-sheets in the cellular condition known as oxidative stress.

Original languageEnglish
Pages (from-to)8014-8023
Number of pages10
JournalJournal of Physical Chemistry B
Issue number24
Publication statusPublished - jún. 23 2011

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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