Molecular mechanisms of radiation induced DNA damage: H-abstraction and beta-cleavage.

Quantum mechanical simulations of hydrogen abstraction by hydroxyl radical from methanol and ethanol yield barriers that agree very well with those measured experimentally. Analysis of the multiconfigurational wavefunction indicates that the strength of the C-H bond is the electronic parameter that has a major contribution to the barrier for H-abstraction. Similar analysis applied to 2-deoxy-D-ribose shows that the strength of a C-H bond together with the steric accessibility of the hydrogen determine that H4 is the most susceptible hydrogen for abstraction by a hydroxyl radical. Quantum mechanical simulations of beta-cleavage show that a concerted mechanism in which a water molecule assists in the bond breaking process is more likely than a SN1 mechanism. However, the polar transition state suggests that the environment of the DNA and the surrounding water will have an important effect on the reaction.

Molecular mechanisms of radiation induced DNA damage: H-addition to bases, direct ionization and double strand break.

Structures and properties of G.(-H) and of TH. were obtained from quantum mechanical calculations. New AMBER parameters for these radicals were obtained to fit their structures and charge distributions. Molecular mechanics simulations of the conformational changes induced in a 12-mer of DNA, d(CGCGAATTCGCG), by these radicals show that the distances between the base and the C2' of the sugar becomes shorter. Such changes suggest that the base radical can abstract the H2' and transfer the radical from the base to the sugar. Once the radical becomes centered on the sugar a strand break can follow. A simultaneous formation of guanine and thymine radicals on opposite strands may lead to a double strand break.