Probing Charge Transport in Oxidatively Damaged DNA Sequences under the Influence of Structural Fluctuations

Abstract

We present a detailed study of the charge transport characteristics of double-stranded DNA oligomers including the oxidative damage 7, 8-dihydro-8-oxoguanine (8-oxoG). The problem is treated by a hybrid methodology combining classical molecular dynamics simulations and semiempirical electronic structure calculations to formulate a coarse-grained charge transport model. The influence of solvent-and DNA-mediated structural fluctuations is encoded in the obtained time series of the electronic charge transfer parameters. Within the Landauer approach to charge transport, we perform a detailed analysis of the conductance and current time series obtained by sampling the electronic structure along the molecular dynamics trajectory, and find that the inclusion of 8-oxoG damages into the DNA sequence can induce a change in the electrical response of the system. However, solvent-induced fluctuations tend to mask the effect, so that a detection of such sequence modifications via electrical transport measurements in a liquid environment seems to be difficult to achieve. I n aerobic organisms, oxidative DNA damage frequently occurs during normal metabolism and upon exposure to light or other ionizing radiation. 7,8-Dihydro-8-oxoguanine (8-oxoG) is one of the most common forms of oxidative DNA damage found in human cells, where a H8 atom in guanine is replaced by an O8 atom, and a H7 atom is added to N7 ( Figure 1). When DNA polymerase encounters 8-oxoG during the DNA replication process, it frequently inserts a mismatched base (adenine) instead of cytosine, leading to G:C → T:A transversions, 1 which are commonly found in mutations associated with age-related diseases and human cancers. Although distinct changes were found in the backbone structure of a 25-base single-stranded DNA (ssDNA) with single 8-oxoG substitutions by Fourier transform-infrared analysis, 3 it has been known that 8-oxoG:C base-pairs have only a minor effect on double-stranded DNA (dsDNA) structure and stability.4,5 Thus, there is an intriguing question as to how the DNA repair enzyme locates 8-oxoG lesions within the entire human genome. In a recent experiment, Markus et al. 6 suggested that 8-oxoG has unique electronic properties and that modulations in the electronic properties might be related to the mechanism of recognizing lesions. They used laser-based methods to investigate various oligomers adsorbed on gold substrates as self-assembled monolayers, and found that the highest occupied molecular orbital (HOMO) appears at a higher energy when 8-oxoG is inserted into the sequence than in unmodified oligomers. The electronic property changes induced by the 8-oxoG lesions suggest the possibility of detecting in vitro 8-oxoG in a DNA sequence by examining the modification of its electrical response; this is expected to have high relevance in, e.g., the development of biosensors based on modifications of the electrical response. 7,8 Electrical detection of an 8-oxo-deoxyguanosine was proposed by Tsutsui et al. 9 by measuring the tunneling cur...

Modeling Charge Transport and Dynamics in Biomolecular Systems

“…In this section, a methodology [81][82][83][85][86][87][88] is described which uses a hybrid approach based on a combination of molecular dynamics simulations and electronic structure calculations with a mapping of the time-fluctuating electronic structure along the MD trajectory onto coarse-grained transport models. The key issue is that in this way the number of free parameters in the model formulation is reduced to a large extent.…”

“…We will first describe the strategy used to calculate in a very efficient way the electronic structure of an arbitrary DNA sequence (the method can be of course applied to other biomolecular systems or to organic stacks) [81][82][83][85][86][87][88]. The immediate goal is to map the electronic structure onto a tightbinding model with time-dependent electronic coupling and onsite energies.…”

“…The present paper will introduce such a methodology which has been recently developed [81][82][83][85][86][87][88]. This approach allows to consider the influence of structural fluctuations and solvent effects onto the electronic structure of DNA oligomers.…”

Modeling charge transport in DNA using multi‐scale methods

“…Without going into details, we like to mention other studies performed within the previously described approach: (i) the influence of mismatches in the nucleobase sequence on the electrical response of DNA oligonucleotides (), (ii) the possibility to detect oxo‐guanosine modifications in double‐stranded DNA via electrical transport measurements (), and (iii) the charge transport properties of G4‐DNA ().…”

Treatment of time‐dependent effects in molecular junctions

“…On the theoretical side, these effects and phenomena require methods which are able to compute transport properties such as current and noise in time‐dependent scenarios efficiently and accurately . Another source of external stimuli on the current are surrounding fluctuating solvent molecules leading to strongly time‐dependent effects . In many of these cases, the fluctuations are large in amplitude and rapidly varying.…”