Quantum Chemical Analysis of the Unfolding of a Penta-alanyl 3_(10)-Helix Initiated by HO~·, HO2~· and O2~(-·)

摘要

In order to elucidate the mechanisms of radical initiated unfolding of a helix, the thermodynamic functions of hydrogen abstraction from the C_α ,C_β, and amide nitrogen of Ala~3 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 (ΔH°), Gibbs free energy (AG°), and entropy (ΔS°), of the reactants and products of these reactions were computed with A5 in the 3_(10)-heIicaI (A5_(Hel)) and fully extended (A5eis) 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_α, followed by the C_β, then amide N in a model helix. The secondary structure has a strong influence on the bond dissociation energy of the H-C_α, 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 3_(10)-helix, protect the peptide from radical attack by hindering the potential electron derealization at the C_α 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 A5_(Hel) and the formation of A5_(Ext). 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.