Probing the interactions of the solvated electron with DNA by molecular dynamics simulations: bromodeoxyuridine substituted DNA.

Solvated electrons ((e-)(aq)) are produced during water radiolysis and can interact with biological substrates, including DNA. To augment DNA damage, radiosensitizers such as bromo-deoxyuridine (BUdR), often referred to as an "electron affinic radiosensitizer", are incorporated in place of isosteric thymidine. However, little is known about the primary interactions of (e-)(aq) with DNA. In the present study we addressed this problem by applying molecular modeling and molecular dynamics (MD) simulations to a system of normal (BUdR.A)-DNA and a hydrated electron, where the excess electron was modeled as a localized (e-)(H2O)6 anionic cluster. Our goals were to evaluate the suitability of the MD simulations for this application; to characterize the motion of (e-)(aq) around DNA (e.g., diffusion coefficients); to identify and describe configurational states of close (e-)(aq) localization to DNA; and to evaluate the structural dynamics of DNA in the presence of (e-)(aq). The results indicate that (e-)(aq) has distinct space-preferences for forming close contacts with DNA and is more likely to interact directly with nucleotides other than BUdR. Several classes of DNA - (e-)(aq) contact sites, all within the major groove, were distinguished depending on the structure of the intermediate water layer H-bonding pattern (or its absence, i.e., a direct H-bonding of (e-)(aq) with DNA bases). Large-scale structural perturbations were identified during and after the (e-)(aq) approached the DNA from the major groove side, coupled with deeper penetration of sodium counterions in the minor groove.