Developing design guidelines for controlling charge transport in DNA.

The initial studies of the dynamics of photoinduced charge separation conducted in our laboratories 20 years ago found strongly distance-dependent rate constants over short distances but failed to detect intermediates in the transport of positive charge (holes). These observations were consistent with the single-step superexchange or tunneling mechanism that had been observed for numerous donor-bridge-acceptor systems at that time. Subsequent studies found weak distance dependence for hole transport over longer distances in DNA, characteristic of incoherent hopping of either localized or delocalized holes. The introduction of synthetic DNA capped hairpin constructs possessing hole donor and acceptor chromophores (or purine bases) at opposite ends of a base-pair domain made it possible to determine the time required for transit of charge from one chromophore to the other and, in some cases, to distinguish between the transit time and the much faster initial charge injection time. These studies eliminated conventional tunneling as a viable mechanism for charge transport in DNA except at very short donor-acceptor separations; however, they did not establish the presence or nature of intermediates in the charge separation process. Recent studies in our laboratories have succeeded in identifying key intermediates as well as untangling the dynamics and efficiency of the charge separation process from start to finish. The dynamics of the initial charge injection process is dependent upon both its free energy and the stacking of the hole donor chromophore and adjacent purine base. The transport of positive charge (holes) over multiple base pairs in duplex DNA occurs most efficiently via repeating adenine bases, known as A-tracts. The transit time across an A-tract is strongly dependent upon the free energy for hole injection, whereas the efficiency of charge separation depends on the competition between charge delocalization and charge recombination in the contact radical ion pair. The guanine cation radical has been detected both by femtosecond transient absorption and by stimulated Raman spectroscopies when the guanine is located near the chromophore employed for hole injection into an A-tract. Replacement of guanine by its derivative 8-phenylethynylguanine (EG), permits tracking of hole transport across longer poly(purine) sequences as a consequence of the stronger transient absorption and stimulated Raman scattering for EG+• vs G+•. We have recently obtained evidence based on femtosecond transient absorption spectroscopy for the formation of delocalized A-polarons in A-tracts possessing four or more A-T base pairs. Similar methods have been used to track hole transport across less-common DNA structures including diblock and triblock poly(purines), locked nucleic acids, three-way junctions, and G-quadruplexes. Similar methods are have been applied to the study of photoinduced electron transport in DNA.

Modeling hole transfer in DNA: Low-lying excited states of oxidized cytosine homodimer and cytosine–adenine heterodimer

Structural and dynamical disorder and charge transport in DNA

We investigate propagation of a charge carrier along intrinsically dynamically disordered double-stranded DNA. This is realized by the semiclassical coupling of the charge with a nonlinear lattice model that can accurately describe the statistical mechanics of the large amplitude fluctuations of the base pairs leading to the thermal denaturation transition of DNA. We find that the fluctuating intrinsic disorder can trap the charge and inhibit polaronic charge transport. The dependence of the mean distance covered by the charge carrier until its trapping, as a function of the energy of the fluctuations of the base pairs is also presented.

Charge transport in DNA

Theoretical understanding of experimental data on charge transport in DNA is a very complicated problem which can be affected by many factors. Instead of going into microscopic details, we investigate a model with a minimal set of parameters for double-stranded poly(G)-poly(C) DNA molecules and analyze some general physics of charge conduction in quasi-one-dimensional molecules. We discuss the contact effect due to coupling between the molecule and electrodes the charging effect due to the Coulomb interaction within the molecule, and the disorder effect due to randomly distributed ions and twisting distortion. These effects result in different transport behavior, all of which can be found in the experimental literature.

Given the success of the polaron model based on solvation in accounting for the width of a hole polaron on an all-adenine (A) sequence on DNA, we extend the calculations to other sequences. We find excellent agreement with the free energy differences measured by Lewis et al. (J. Am. Chem. Soc. 2000, 122, 12037-12038) between a guanine (G) cation and a pair of bases, GG, or a triple of bases, GGG, in all cases surrounded by As, by treating AGGA and AGGGA as solvated polarons. There is additional support for hole polaron formation in DNA from experiments in which oxidative damage due to injected holes is investigated in sequences involving Gs and As. Theory and comparison with transport measurements on repeated sequences involving multiple thymines (Ts) or combinations such as ATs or GCs, where C is cytosine, led to the suggestion that the basic sequences in these cases must be polarons whose wave functions have substantial amplitudes on both chains in a duplex. The size of an electron polaron in DNA is predicted to be similar to that of a hole polaron, approximately 4 or 5 bases. Although experiments have shown that polaron hopping is the dominant mode of charge transport in DNA with repeated sequences such as AGGA, further investigations, particularly of temperature dependence of site energies and transfer integrals, are needed to determine to what extent hole transport takes place by polaron hopping for arbitrary DNA sequences.

Here we describe studies of metallointercalators bound to DNA. These octahedral transition metal complexes primarily bind noncovalently by stacking within the DNA helix. Given the rich photophysics and photochemistry of the ruthenium and rhodium complexes we employ, we have used a variety of biophysical studies to characterize their interactions with DNA. X‐ray crystallography has also provided atomic resolution detail as to their binding to the duplex. Complexes have been designed that target DNA with high specificity. We have, for example, designed metal complexes that bind specifically to mismatched sites in the DNA duplex, and these have found application in the detection of single nucleotide polymorphisms and studies of mismatch repair deficiency. The photophysical properties of the metal complexes along with their intercalative stacking have been useful in particular as tools to characterize long‐range charge transport in DNA. Using metallointercalators tethered to the duplex, oxidative damage to DNA from a distance has been demonstrated. The metallointercalators may serve as models for DNA‐binding proteins, not only in binding DNA sites with high specificity, but also in carrying out electron transfer chemistry mediated by the DNA base‐pair stack. Certainly these metallointercalators have proven to be powerful probes of this chemistry.

Despite great efforts in the experimental and theoretical investigation of charge migration in DNA oligomers, no unified explanation of the microscopic mechanisms governing charge transfer/transport has been achieved up to date. The complexity of this bio‐molecule as well as the variety of factors that influence charge transfer/transport (solvent, base dynamics, nucleobase sequence, metal‐molecule contact) make the available experimental data difficult to analyze unambiguously. Thus, theory and computation play a prominent role by guiding experimental studies and providing them with well‐defined predictions concerning the role of all these factors. A fundamental problem in such systems is the strong coupling of electronic and structural degrees of freedom, which makes a treatment based on standard perturbation theory unfeasible in general. This review focuses on various methodological approaches to which the authors have strongly contributed. The advantage of these approaches relies on an efficient combination of accurate electronic structure calculations, classical molecular dynamics, and charge transport approaches, to describe charge migration in complex (bio)molecular systems.

DNA conjugates containing adjacent duplex and guanine quadruplex assemblies have been designed to explore charge transport into quadruplex architectures. The quadruplex assemblies have been characterized structurally using circular dichroism and by assaying for chemical protection. Using an intercalating rhodium photooxidant, noncovalently bound or tethered to the duplex end, oxidizing radicals are found to be trapped in the folded quadruplex. Damage is observed almost exclusively at the external tetrads of the quadruplex. Little damage of the center tetrad is observed, due most likely to lowered efficiency of radical trapping within the quadruplex core. This pattern of damage is distinct from that observed for repetitive G sequences within duplex DNA. The data indicate, furthermore, that in the conjugates examined, the guanine quadruplex provides a more effective trap than a 5'-GG-3' guanine doublet within duplex DNA. Within these assemblies, sufficient base-base overlap must exist at the duplex/quadruplex junction to allow for charge migration. This funneling of damage to the quadruplex, as well as the unique pattern of damage within the quadruplex, requires consideration with respect to the analysis of oxidative DNA damage within the cell.

A functionality of on/off switching to regulate conductivity should be among the prerequisites for the utilization of DNA duplex as a conducting material. We have reported that variation of temperatures can regulate the triplex formation and dissociation, thereby regulating charge transport in DNA. Based on this result, the on/off switching of conductivity at dual triplex forming sites in DNA was attempted, using two types of oligonucleotide (ODNs) with different strand lengths. Variation of temperatures produced DNA duplexes without any triplex site and with single and double triplex sites, by which the intramolecular charge transport in DNA duplex could be regulated at the respective triplex-forming sites. This may promote the utility of DNA duplex as a potential constituent of electronic nanodevices.

Suppression of DNA-Mediated Charge Transport by BamHI Binding

Damage to DNA is often caused by oxidative reactions. In one such process, an electron is lost from a base, forming its radical cation. Further reaction of the radical cation can lead to permanent change, which results in mutation. This Account is a report on oxidative damage to DNA caused by irradiation of anthraquinone derivatives, which are either randomly bound to the DNA or attached to it covalently at specific locations. Radical cations introduced in the DNA by the excited quinone cause damage both near to it and far away. We describe a mechanism for long-range charge transport in DNA that depends on its spontaneous structural distortion, which we call phonon-assisted polaron hopping. This mechanism, and its extension, provides a framework for understanding the reactions and charge-transport properties of DNA.

A model of hole transfer in DNA molecules has been proposed, which takes into account changes in the reorganization energy and orbital coupling between the neighboring bases during the charge transfer in different molecular sequences. It is shown that the rate of hole transfer by the superexchange and hopping transfer mechanisms is limited by the relaxation of the geometries of nucleobases participating in charge migration and the dynamics of solvent molecules. The rate of charge transfer in the DNA molecule is found to be dependent on the height of the potential barriers between the nucleotide and the molecular sequences. The inclusion of the interchain charge transfer, which is characterized by weak coupling between the nucleotides located in opposite strands, does not affect the general charge transport in DNA. The increase in the number of the parallel components of the hopping mechanism leads to a rise in the charge transfer rate in the double helix.

In Chap. 1, Cuniberti et al. have presented a review of theoretical models that are used for simple, tight-binding-based analysis of charge transport in DNA. These simplified models for the DNA strand can offer insights albeit qualitatively, into the intrinsic transport characteristics, statistical properties, sequence dependence and also the effects of solution and the environment.