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 center dot A)-DNA and a hydrated electron, where the excess electron was modeled as a localized e(-)(H(2)O)(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.