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

Abstract

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.