Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases: a computational investigation of radiation damage

TY - JOUR

T1 - Insight into the mechanism of the initial reaction of a OH-radical with DNA/RNA nucleobases

T2 - a computational investigation of radiation damage

AU - Milhøj, Birgitte Olai

AU - Sauer, Stephan P. A.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5.03×10−12 cm3 molecules−1 s−1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.

AB - Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X-D/6-311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10−12, 5.64×10−11, 2.01×10−11, and 5.03×10−12 cm3 molecules−1 s−1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.

KW - Faculty of Science

KW - Radiation Damage

KW - DNA

KW - Adenine

KW - OH radical

KW - Kinetics

KW - DFT calculations

KW - Thermodynamics

KW - Quantum Chemistry

KW - Computational Chemistry

KW - Thymine

KW - Uracil

KW - Guanine

KW - Cytosine

UR - http://ing.dk/artikel/danske-forskere-finder-den-kemiske-forklaring-paa-partikelterapi-180682

UR - http://chem.ku.dk/om/news/newslist/hadron/

U2 - 10.1002/chem.201503107

DO - 10.1002/chem.201503107

M3 - Journal article

C2 - 26494117

SN - 1521-3765

VL - 21

SP - 17786

EP - 17799

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 49

ER -