160. D. L. Reid, G. V. Shustov, D. A. Armstrong, A. Rauk, M. N. Schuchmann, M. S. Akhlaq, and C. von Sonntag, H-Abstraction from Thiols by C-Centered Radicals. An Experimental and Theoretical Study, Phys. Chem. Chem. Phys. in press (accepted (2001/11/05.) - Abstract
157. A. Rauk, D. A. Armstrong, and J. Berges, Glutathione Radical: Intramolecular H Abstraction by the Thiyl Radical, Can. J. Chem.,79, 405-417 (2001) - Abstract
156. A. Rauk, D. A. Armstrong, and D. P. Fairlie, Is Oxidative Damage By Beta Amyloid and Prion Peptides Mediated by Hydrogen Atom Transfer from Glycine Alpha-Carbon to Methionine Sulfur within Beta-Sheets?, J. Am. Chem. Soc. 122, 9761-9767 (2000) - Abstract
153. A. Rauk and D. A. Armstrong, Influence of beta-Sheet Structure on the Susceptibility of Proteins to Backbone Oxidative Damage: Preference for alpha-C-Centered Radical Formation at Glycine in Antiparallel beta-Sheets, J. Am. Chem. Soc, in press (accepted 2000/02/02) - Abstract
150. A. Rauk, D. Yu, J. Taylor, G. V. Shustov, D. A. Block, and D. A. Armstrong, A Comparison of the alpha-C-H Bond Enthalpies of Amino Acid Residues in a Protein Model Environment, Biochemistry, 38, 9089-9096 (1999) - Abstract
146. G. V. Shustov and A. Rauk, Dioxirane Oxidation of Nitrosamines. An Ab Initio Study, Can. J. Chem., 77, 74-85 (1999).
143. D. A. Block, D. Yu, D. A. Armstrong, and A. Rauk, On the Influence of Secondary Structure on the a-C-H Bond Dissociation Energy of Proline Residues in Proteins: a Theoretical Study, Can. J. Chem., 76, 1042-1049 (1998)..
142. M. Jonsson, D. D. M. Wayner, D. A. Armstrong, D. Yu, and A. Rauk, On the Thermodynamics of Peptide Oxidation, J. Chem. Soc. Perkin II, 1967-1972 (1998).
141. G. V. Shustov and A. Rauk, A Theoretical Study of Oxidation of CH Bonds in Homo- and Heterosubstituted Alkanes by Dioxirane as a Model of the Dioxirane Oxidation of Peptides, J. Org. Chem.63, 5413-5422 (1998).
140. D. A. Armstrong, D. Yu, and A. Rauk, Oxidative Damage to Cysteine in Proteins: an Ab Initio Study of the Radical Structures, C-H, S-H, and C-C Bond Dissociation Energies, and Transition Structures for H Abstraction by Thiyl Radicals, J. Am. Chem. Soc. 120, 8848-8855 (1998). - Abstract
135. D. D. M. Wayner, K. B. Clark, A. Rauk, D. Yu, and D. A. Armstrong, C-H Bond Dissociation Energies of Alkyl Amines, J. Am. Chem. Soc., 119, 8925-8932 (1997).
131. D. A. Armstrong, D. Yu, and A. Rauk, Gas Phase and Aqueous Thermochemistry of Hydrazine and Related Radicals and the Energy Profiles of Reactions with H. and OH.: An Ab Initio Study, J. Phys. Chem. 101, 4761-4769 (1997).
128. A. Rauk, D. Yu, and D. A. Armstrong, Toward Site Specificity of Oxidative Damage in Proteins: C-H and C-C Bond Dissociation Energies and the Reduction Potentials of the Radicals of Alanine, Serine, and Threonine - an Ab Initio Study, J. Am. Chem. Soc. 119, 208-217 (1997). - Abstract
121. D. A. Armstrong, D. Yu, and A. Rauk, Oxidative Damage to the Glycyl a-Carbon in Proteins: an Ab Initio Study of the C-H Bond Dissociation Energy and the Reduction Potential of the C-Centered Radical, Can. J. Chem., 76, 1192-1199 (1996).
117. D. Yu, D. A. Armstrong and A. Rauk, The Structures and Relative Energies of Formamide (H2NCHO) and Radical Ions H2NCHO.+, H2NCOH.+, and H3NCO.+, Chem. Phys. 202, 243 (1996).
109. A. Rauk, D. Yu, P. Borowski, and B. Roos, CASSCF, CASSPT2, and MRCI Investigations of Formyloxyl Radical (HCOO.), Chemical Physics, 197, 73-80 (1995) - reprints not ordered.
105. D. Yu, A. Rauk, and D. A. Armstrong, The Solution Thermochemistry of the Radicals of Glycine, J. Chem. Soc. Perkin 2, 553 - 560 (1995).
104. D. Yu, A. Rauk, and D. A. Armstrong, The Radicals and Ions of Glycine: An ab initio Study of the Structures and Gas Phase Thermochemistry , J. Am. Chem. Soc. 117, 1789 - 1796 (1995).
99. D. Yu, A. Rauk, and D. A. Armstrong, The Radicals and Ions of Formic and Acetic Acids Acids: An ab initio Study of the Structures and Gas and Solution Phase Thermochemistry, J. Chem. Soc. Perkin 2, 2207 - 2215 (1994).
97. A. Rauk, D. Yu, and D. A. Armstrong, Carboxyl Free Radicals: Formyl and Acetyl Revisited, J. Am. Chem. Soc., 116, 8222-8228 (1994).
93. D. Yu, A. Rauk, and D. A. Armstrong , Gas and solution phase thermochemistry and transition energies of NH2., NH3+., and their aquo complexes: An ab initio study. Can. J. Chem., 72, 471-483 (1994)
92. A. Rauk, D. A. Armstrong, and D. Yu, The Lifetime of Gas Phase CO2.- and N2O.- Calculated from the Transition Probability of the Autodetachment Process A- - A + e-. Int. J. Chem. Kinet., 26, 7 (1994)
Abstract: The Radical Model of Alzheimer’s Disease (AD)
is presented in some detail. The model provides a unified picture
for the role of the amyloid beta peptide (Ab),
Met35, copper ions, oxygen, beta sheet secondary structure, and the generation
of hydrogen peroxide, in mediating oxidative stress in AD. It predicts
a role for glycyl radicals as long-lived species which can transport the
damage into cell membranes and initiate lipid peroxidation.
Previous work has established the thermodynamic and kinetic viability of
most of the steps. In the present work, QM/MM and Amber calculations
reveal that self assembly of antiparallel b-sheet
which brings Met35 into the required close proximity to a glycine residue
is more likely if the residue is Gly29 or Gly33, than any of the other
four glycine residues of Ab.
- Return to Selected Publications
Abstract: The hydrogen atom abstraction by a series of
carbon-centered radicals from methanethiol is examined in the gas phase
and in aqueous solution using quantum mechanical calculations. The
gas phase reactions are modeled at the ab initio B3LYP/6311+G(d,p) level,
coupled with an empirical correction to the enthalpy of reaction and activation.
The solvent effects are evaluated by two different continuum models (SCIPCM,
CPCM), coupled with a novel approach to the calculation of the solution
phase entropy. The reaction is discussed in terms of the charge and
spin polarization in the transition state, as determined by AIM analysis,
and in terms of orbital interaction theory. Rate constants, calculated
by transition state theory are in good agreement with the available experimental
data.- Return to Selected Publications
Abstract: Ab initio computations (B3LYP/6-31G(D)) were used to predict transition structures and energies of activation for intramolecular H atom transfer to a thiyl radical (RS.) from the aC-H bonds of glutathione 1 and from the model compounds, N-formylcysteinylglycine 2 and N-(2-thioethanyl)-g-glutamine 3. For each compound, transition structures were located by in vacuo calculations on the neutral non-zwitterionic system. Thermodynamic functions derived at the same level and single point calculations at the B3LYP/6-311+G(3df,2p) level, were used to derive free energies of activation (DG?) and reaction (DGo). For abstraction of the aC-H(Gly) by the thiyl radical in the gas phase, DG? = 134 kJ mol-1 if the amide link to Gly is in the more stable (Z)-configuration and DG? = 52 kJ mol-1, if it is in the less stable (E)-configuration. The isomerization of the amide group requires about 95 kJ mol-1. Previous studies had indicated that for intramolecular reaction of the thiyl radical at aC-H(Cys), DG? = 110 kJ mol-1. The lowest energy pathway for intramolecular H transfer to the thiyl radical is from aC-H(Gln), DG? = 37 - 42 kJ mol-1, and corresponds rather well with experimental results in solution, DG? = 43 kJ mol-1. The calculated free energy change for the equilibrium between thiyl and aC forms of the glutathione radical, DGo = -54 kJ mol-1. The value estimated from experimental data is DGo = -37 kJ mol-1. The agreement between the energies from theory in the gas phase and experiment in solution suggests that the free energies of solvation of reactant thiyl radical, transition structures for H abstraction, and the product aC-centred radical, are very similar. The effects of solution were estimated by two continuum models, SCIPCM and COSMO. The SCIPCM model yields results very similar to the gas phase, predicting a modest lowering of the activation free energy. The results from the COSMO method were inconclusive as to whether a rate enhancement or decrease could be expected.- Return to Selected Publications
Abstract: Methionine in glycine rich regions of both beta amyloid
peptide and prion peptide is thought to be crucial to their neurotoxic
properties. We postulate here a role for methionine in the propagation
of oxidative damage. The S-H bond dissociation enthalpies, BDE(S-H)s,
of dimethylsulfonium ion (CH3)2SH+, and
a S-protonated methionine residue of a polypeptide strand are estimated
to be 351 kJ mol-1 and 326 - 331 kJ mol-1 , respectively,
by the application of calculations at the B3LYP level with large basis
sets. These species are direct products of H atom abstraction by
radical cations of sulfides. The reactions between a glycine residue
and the radical cations of (CH3)2S and Met were investigated,
and the transition structures for H atom transfer located. The results
suggest that it is thermodynamically feasible for the S-ionized form of
Met to cause oxidative damage at the aC-H
site of almost any amino acid residue of a nearby polypeptide strand (BDE(aC-H)
= 330 - 360 kJ mol-1), or to nearby lipids with a bis(allylic)
methylene group (BDE(C-H) = 335 kJ mol-1). However, a
key observation is that when the Met residue is incorporated into an antiparallel
b-sheet,
only a Gly residue is exposed and susceptible to oxidation at the aC-H
site. Furthermore, the Gly must lie on a different strand of the
b-sheet to that containing Met, and must be
part of a (5,5), rather than a (3,3) cycle. The same considerations apply
to the methyl-deprotonated form of the sulfide radical cation but not the
methylene-deprotonated form. These findings suggest a possible mechanism
for generating and propagating oxidative damage via a Met residue of the
Ab peptide of Alzheimer's Disease and of the
prion peptide of Creutzfeldt-Jakob Disease. To our knowledge, this
is the first proposed mechanism that accounts for the radical damage in
either of these diseases and requires peptide b-sheets,
and amino acids, methionine and glycine.- Return to
Selected Publications
Abstract: Ab initio calculations at the B3LYP/6-31G(d) level
of theory were carried out on selected cyclic hydrogen bonded dimers of
glycine and alanine as models for b-sheets,
and on the aC-centered radicals derived
from them. The structures mirrored the cycles found in the H-bonded
network of parallel and antiparallel b-sheet
secondary structure, and were optimized both with and without enforcement
of constraints on the F,Y torsion angles.
Transition structures for the migration of an H atom from an aC
site to another aC site or to an
S atom were located. It was found that the presence of a hydrogen
bonded strand of a b-sheet has little effect
on the aC-H bond dissociation enthalpy
(BDE) of glycine, but raises the BDE of other residues by a significant
amount. The parallel b-sheet structure
and F,Y angles lead to a significant increase
in BDE relative to the random coil structure, due to loss of captodative
stabilization. The antiparallel b-sheet
structure and F,Y angles do not lead to a significant
increase in BDE. All residues incorporated in b-sheet
secondary structure, with the exception of glycine, are protected from
oxidative damage because the aC-H
bond is internal to the sheet and inaccessible to oxidizing radicals.
Glycine is susceptible to oxidative damage because it has a second aC-H
bond which is exposed. Among residues in secondary structures, only
glycine is susceptible to damage by weak oxidants such as thiyl radicals
and superoxide, provided it is in an antiparallel b-sheet.
Radical damage may propagate readily from one strand to another above the
b-sheet,
but not within the b-sheet.
b-Sheet
structure narrows the difference between the glycyl aC-H
BDE and S-H BDE and facilitates interstrand H atom transfer between the
glycyl aC site and the S atom of
cysteine.- Return to Selected Publications
Abstract: The bond dissociation enthalpies (BDE) of all of the
amino acid residues, modelled by HC(O)NHCH(R)C(O)NH2 (PH(Res)) were determined
at the B3LYP/6-31G(D) level, coupled with isodesmic reactions. The
results for neutral side chains with f, y
angles ~180o,~180o in ascending order, to an expected
accuracy of " 10 kJ mol-1,
are: Asn 326; Cystine 330; Asp 332; Gln 334; Trp 337; Arg 340; Lys
340; Met 343; His 344; Phe 344; Tyr 344; Leu 344; Ala 345; Cys 346; Ser
349; Gly 350; Ile 351; Val 352; Glu 354; Thr 357; Pro-cis 358; Pro-trans
369. These BDEs are smaller than those of typical secondary or tertiary
C-H bonds due to the phenomenon of captodative stabilisation. The stabilisation
is reduced by changes in the f,
y
angles. As a result the BDEs increase by about 10 kJ mol-1
in b-sheet and 40 kJ mol-1 in a-helical
environments, respectively. In effect the aC-H
BDEs can be "tuned" from about 345 to 400 kJ mol-1 by adjusting
the local environment. Some very significant effects of this are
seen in the current literature on H transfer processes in enzyme mechanisms
and in oxidative damage to proteins. These observations are discussed
in terms of the findings of the present study.- Return
to Selected Publications
Abstract: Ab initio computations (B3LYP/6-31G(D), coupled
with isodesmic reactions) were used to predict bond dissociation energies
(BDEs) of aC-H (D(aC-H)) and other bonds of cysteine, both as free
neutral amino acid (AH(Cys)) and as a residue in a model peptide
(PH(Cys)). The latter was intended to mimic the environment
in proteins. Transition structures were located for intermolecular
and intramolecular H atom transfer to a thiyl radical (RS.) from a sulfhydryl
group (RSH) or the aC-H bond. The predicted BDEs, at 298 K,
in kJ mol-1 to an estimated accuracy of 10 kJ mol-1 for the fully optimized
system are: AH(Cys), D(aC-H) = 322, D(bC-H) = 390, D(aC-C)=
264, D(S-H)= 373; PH(Cys), D(aC-H)= 346,
D(bC-H)= 392, D(aC-C)= 287, D(S-H)= 367. In PH(Cys)
with torsional angles constrained to simulate b-sheet and a-helical secondary
structure, rises to 359 and 376, respectively. Cystine in the peptide
environment was modelled by replacing -SH by -SSCH3, PH(CysSCH3),
D(aC-H) = 330. Enthalpies of activation for intermolecular H transfer
to RS. were found to be low: from RSH, 12 kJ mol-1; from aC-H, about 25
kJ mol-1, the latter being consistent with reaction rates of the order
of 105 M-1 s-1. The enthalpic barrier for intramolecular H transfer
from aC-H to -S. within a single cysteine residue is too high (83 - 111
kJ mol-1) for this to be a competitive process.- Return
to Selected Publications
128. Toward Site Specificity of Oxidative Damage in Proteins: C-H and C-C Bond Dissociation Energies and the Reduction Potentials of the Radicals of Alanine, Serine, and Threonine - an Ab Initio Study
Abstract: High level ab initio computations were used to characterise the parent species and radicals for alanine, serine and threonine, both as free neutral amino acids (AH) and as residues in model peptides (PH) intended to mimic the mid chain environment in proteins. The ab initio energies were used in isodesmic reactions to predict bond dissociation energies (BDEs, ) at 298 K, in kJ mol-1 to an estimated accuracy of 10 kJ mol-1. For the fully optimized systems the values of are: AH(Gly), 331; AH(Ala), 317; AH(Ser), 327; AH(Thr), 328; PH(Gly), 348; PH(Ala), 344; PH(Ser), 348; PH(Thr), 356. All of the values are less than the BDE of a typical SH bond (370 kJ mol-1), as in cysteine or glutathione (GSH), a result that suggests that oxidative damage at the site will not be repaired efficiently by the mechanism of H donation from GSH. Values of in typical peptide conformations, such as -sheet and -helical secondary structure, were estimated by constraining the Ramachandran dihedral angles phi, and psi, to values typical of these structures. Thus values are estimated as: PH(Gly), 361; PH(Ala), 359; PH(Ser), 347; PH(Thr), 356 in the beta-sheet conformation, and: PH(Gly), 402; PH(Ala), 384; PH(Ser), 381; PH(Thr), 363 in the alpha-helix conformation. Hence, these residues are also expected to be susceptible to irreparable oxidative damage in beta-sheet structures, but Gly, Ala and Ser residues in alpha-helical regions should be less susceptible to damage and should be repairable by GSH. A consideration of reduction potentials calculated from the BDEs and entropies derived from the ab initio results leads to the same conclusions and indicates that certain radicals other than OH. that occur in cells (e.g. ROO.) may also cause oxidative damage to beta-sheet structures. Ab initio calculations were also done for the C-centered radicals formed by removal of H from the side chains. These showed that there is a marked increase in the ease of abstraction of this H in the series Ala, Ser,Thr. - Return to Selected Publications