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ABSTRACT: Recent studies using ab initio calculations have-shown that C-alpha-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of C-alpha-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the C-alpha-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the C-alpha-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the C-alpha-containing residue (Alr) are preferred and these conformations increase the formation of gamma-, alpha-, and pi-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 3(10)-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the C-alpha of peptide and protein residues.
Journal of Chemical Theory and Computation 08/2012; 8(8):2569-2580. · 5.22 Impact Factor
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ABSTRACT: In this study, the thermodynamic functions of hydrogen abstraction from the C(α) and amide nitrogen of Gly(3) in a homo-pentapeptide (N-Ac-GGGGG-NH(2); G5) by HO(●), HO(2)(●), and O(2)(-●) were computed using the Becke three-parameter Lee-Yang-Parr (B3LYP) density functional. The thermodynamic functions, standard enthalpy (ΔH°), Gibbs free energy (ΔG°), and entropy (ΔS°), of these reactions were computed with G5 in the 3(10)-helical (G5(Hel)) and fully-extended (G5(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 conductor-like polarizable continuum model implicit water model. H abstraction is more favorable at the C(α) than at the amide nitrogen. The secondary structure of G5 affects the bond dissociation energy of the H-C(α), but has a negligible effect on the dissociation energy of the H-N bond. The HO(●) radical is the strongest hydrogen abstractor, followed by HO(2)(●), and finally O(2)(-●). The secondary structure elements, such as H-bonds in the 3(10)-helix, protect the peptide from radical attack by disabling the potential electron delocalization at the C(α), which is possible when G5 is in the extended conformation. The unfolding of the peptide radicals is more favorable than the unfolding of G5(Hel); however, only the HO(●) can initiate the unfolding of G5(Hel) and the formation of G5(Ext)(●). These results are relevant to peptides that are prone to undergoing transitions from helical structures to β-sheets in the cellular condition known as "oxidative stress" and the results are discussed in this context.
The Journal of chemical physics 07/2011; 135(3):035101. · 3.09 Impact Factor
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ABSTRACT: 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-NH(2); A5) by HO(•), HO(2)(•), and O(2)(-•) were computed using the B3LYP density functional. The thermodynamic functions, standard enthalpy (ΔH(o)), Gibbs free energy (ΔG(o)), and entropy (ΔS(o)), 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(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-CH(2) and H-N bonds. The HO(•) radical is the strongest hydrogen abstractor, followed by HO(2)(•) and finally O(2)(-•). 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(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.
The Journal of Physical Chemistry B 06/2011; 115(24):8014-23. · 3.70 Impact Factor
