DOI: 10.1002/chem.200400171. Influence of DNA Structure on the Reactivity of the Guanine Radical Cation

Influence of DNA Structure on the Reactivity of the Guanine Radical Cation

10.1002/chem.200400171

Crossref journal-article

Wiley

Chemistry – A European Journal (311)

Abstract

AbstractOxidative damage of DNA via radical cation formation is a common cause of mutagenesis, cancer and of the physiological changes associated with aging. By using state‐of‐the‐art ab initio molecular dynamics simulations, we study the mechanism that guides the first steps of this process. In the mechanism proposed here, guanine, which among the bases has the lowest oxidation potential, and the phosphate backbone play a crucial role. We found that the rate limiting step is the water protolysis. We illuminate the role of the local environment in considerably lowering the barrier. Of particular relevance in this respect is the role of the phosphate backbone.

Bibliography

Gervasio, F. L., Laio, A., Iannuzzi, M., & Parrinello, M. (2004). Influence of DNA Structure on the Reactivity of the Guanine Radical Cation. Chemistry â A European Journal, 10(19), 4846â4852. Portico.

Authors 4

Francesco Luigi Gervasio (first)
Alessandro Laio (additional)
Marcella Iannuzzi (additional)
Michele Parrinello (additional)

References 50 Referenced 63

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{'key': 'e_1_2_4_3_2', 'volume-title': 'DNA Repair Mutagenesis', 'author': 'Friedberg E. C.', 'year': '1995'} / DNA Repair Mutagenesis by Friedberg E. C. (1995)
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10.1021/ja9609821
10.1021/ja991032t
10.1021/ja972331q
10.1021/cr960421s
In fact there is mounting evidence that vacancies can travel very long distances in double helical DNA[12 49 50]and concentrate on G.[13]
10.1016/S1367-5931(02)00364-2
10.1146/annurev.biochem.71.083101.134037
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10.1039/b109204a
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10.1021/jp0212904
{'key': 'e_1_2_4_26_2', 'first-page': '1293', 'volume': '378', 'author': 'Steenken S.', 'year': '1997', 'journal-title': 'Biol. Chem.'} / Biol. Chem. by Steenken S. (1997)
10.3109/10715769209049187
10.1007/b94409
{'key': 'e_1_2_4_29_2', 'volume-title': 'DNA Adducts: Identificarion and Biological Significance', 'author': 'Cadet J.', 'year': '1994'} / DNA Adducts: Identificarion and Biological Significance by Cadet J. (1994)
10.1021/ja016426a
10.1021/ja971728r
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10.1007/978-1-4612-5190-3
In the QM/MM simulations the two subsystems are electrostatically and mechanically coupled as described in ref.[22]The quantum system was terminated at the QM/MM boundary with hydrogen atoms saturating the valence of the boundary atoms. Since these added hydrogen atoms must interact with the quantum but not with the classical sub‐system their electrostatic interaction with the nearby classical atoms was shielded in order to avoid the formation of unphysical hydrogen bonds with the nearby classical atoms. To that end the MM atoms covalently connected to QM atoms are coupled with the quantum system by a Coulomb potential with a set of ESP‐like charges localized on the QM atoms and defined as described in ref. [51]. In this manner pair interactions that have to be shielded can be explicitly excluded from the interaction Hamiltonian.
The functional of choice for most calculations was the BLYP functional.[52 53]Since it was suggested that other “pure” functionals (e.g. HCTH[54 55]) give better results than BLYP for deprotonation and transition state energies [55]in a few cases we repeated the calculations with that functional but the energy differences that we obtained for our system were well within the error bar.[55]The Kohn–Sham orbitals were expanded up to an energy cutoff of 70 Ry and the calculations were made in the local spin density framework (i.e. singly occupied orbitals). The classical region that included all the remaining atoms was treated with the Amber force field.[56]
10.1103/PhysRevB.43.1993
CPMD Copyright IBM Corp 1990–2001 Copyright MPI fuer Festkoerperforschung Stuttgart 1997–2001.
10.1021/jp0496405
10.1039/a801517a
10.1021/ja953370
10.1021/j100203a039
10.1246/bcsj.63.33
Assumingτ≈1.
In reducing conditions this precursor is converted into 2 6‐diamino‐4‐hydroxy‐5‐formamidopyrimidine nucleoside (FapyG).[1]
Calculations on this alternative oxidation pathway are in progress and preliminary results indicate the existence in DNA of a barrier to oxygen attack due to steric hindrance posed by neighboring bases.
10.1021/ja983092p
10.1088/0022-3719/5/13/012
Starting from 300 K the temperature was cooled down to 2 K rescaling the velocities by a factor of 0.99 each step. This procedure while ensuring convergence to a local minimum generally does not allow for major rearrangements of the structure. However in this case we started from a geometry that was already optimized and whose close packing of the atoms taken from the X‐ray crystal structure[34]does not allow much rearrangement of the backbone.

Dates

Type	When
Created	21 years ago (Aug. 20, 2004, 2:45 p.m.)
Deposited	1 year, 10 months ago (Oct. 9, 2023, 11:03 a.m.)
Indexed	1 year, 2 months ago (June 18, 2024, 3:55 p.m.)
Issued	20 years, 11 months ago (Sept. 22, 2004)
Published	20 years, 11 months ago (Sept. 22, 2004)
Published Online	20 years, 11 months ago (Sept. 22, 2004)
Published Print	20 years, 10 months ago (Oct. 4, 2004)

Funders 0

None

BibTeX

@article{Gervasio_2004, title={Influence of DNA Structure on the Reactivity of the Guanine Radical Cation}, volume={10}, ISSN={1521-3765}, url={http://dx.doi.org/10.1002/chem.200400171}, DOI={10.1002/chem.200400171}, number={19}, journal={Chemistry – A European Journal}, publisher={Wiley}, author={Gervasio, Francesco Luigi and Laio, Alessandro and Iannuzzi, Marcella and Parrinello, Michele}, year={2004}, month=sep, pages={4846–4852} }

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