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.

Investigation of Excess‐Electron Transfer in DNA Double‐Duplex Systems Allows Estimation of Absolute Excess‐Electron Transfer and CPD Cleavage Rates

“…Further experiments are required, particularly with different electron acceptors, to better understand the redox potentials and reaction rates in DNA duplexes and the absolute hopping rates. [30][31][32] …”

DNA Radiosensitization: The Search for Repair Refractive Lesions Including Double Strand Breaks and Interstrand Crosslinks

“…Likewise only in scDNA, the e aq¯ preferentially occupied close sites and formed contacts with the two most perturbed thymidines (dT5 and dT7) flanking BrdU. At present, there is no explanation for the disparity of e aq¯ interactions with dsDNA vs. scDNA, other than the different dynamic structure of the isosteric DNA sequences under study, including the dynamics of structured water and Debay-Hückel layers (Gantchev & Hunting, 2008. The exposure of wobble-pair pyrimidine carbonyl groups into the DNA grooves results in excess solvation of the mismatched pairs (Sherer & Cramer, 2004).…”

“…We hypothesized that e − aq may have a restricted access to BrdU when incorporated in a normal DNA duplex, although the Br-atom is partially solvent-exposed in the major groove. To address this issue we applied molecular modeling and nanosecond scale molecular dynamics (MD) simulations, where the excess electron in solution was modeled as a localized e − (H 2 O) 6 anionic cluster (Gantchev & Hunting, 2008. We compared the dynamics and interactions of e − aq with dsDNA containing a normal BrdU•dA pair in the center of the duplex (dsDNA) with that of a wobble DNA containing a single mismatched BrdU^dT pair (scDNA), i.e.…”

“…A B Gantchev & Hunting, (2008 In addition, the incorporated mismatched pairs (T^T or BU^T) alter the dynamics of the neighboring bases due to incomplete 5′-stacking. Together with the narrowing of the minor groove these phenomena bring the two strands closer which creates conditions for crossstrand (cs) stacking and single and multiple cross-strand (cs) H-bonding not only within the mismatched regions, but also encompassing penultimate nucleotides to create extended "zipper-like" motives (Špačková et al, 2000).…”

Solvation dynamics of surface-trapped electrons at NH3 and D2O crystallites adsorbed on metals: from femtosecond to minute timescales

“…5 This wide-spread relevance led to an impressive number of studies on the solvated electron's ground and excited state properties in the solid and liquid phase. Yet, up to now, the precise characteristics of the hydrated electrons remain controversial; the traditional ''cavity model'', 6,7 which describes the excess electron density as being stabilized by a void in the water network, has just recently been challenged by molecular dynamics simulations that predict hydration of the electron even in denser regions of liquid water as opposed to a cavity.…”