DNA as a Molecular Wire: Distance and Sequence Dependence

Article pubs.acs.org/ac

DNA as a Molecular Wire: Distance and Sequence Dependence Chris H. Wohlgamuth, Marc A. McWilliams, and Jason D. Slinker* Department of Physics, The University of Texas at Dallas, 800 W. Campbell Rd., EC 36, Richardson, Texas 75080, United States S Supporting Information *

ABSTRACT: Functional nanowires and nanoelectronics are sought for their use in next generation integrated circuits, but several challenges limit the use of most nanoscale devices on large scales. DNA has great potential for use as a molecular wire due to high yield synthesis, near-unity purification, and nanoscale self-organization. Nonetheless, a thorough understanding of ground state DNA charge transport (CT) in electronic configurations under biologically relevant conditions, where the fully base-paired, double-helical structure is preserved, is lacking. Here, we explore the fundamentals of CT through double-stranded DNA monolayers on gold by assessing 17 base pair bridges at discrete points with a redox active probe conjugated to a modified thymine. This assessment is performed under temperature-controlled and biologically relevant conditions with cyclic and square wave voltammetry, and redox peaks are analyzed to assess transfer rate and yield. We demonstrate that the yield of transport is strongly tied to the stability of the duplex, linearly correlating with the melting temperature. Transfer rate is found to be temperature-activated and to follow an inverse distance dependence, consistent with a hopping mechanism of transport. These results establish the governing factors of charge transfer speed and throughput in DNA molecular wires for device configurations, guiding subsequent application for nanoscale electronics.

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physiological conditions.42 When these criteria are met, good electrical properties are consistently observed from a number of groups.16 Nonetheless, a thorough understanding of ground state DNA charge transport (CT) in electronic configurations under biologically relevant conditions, where the fully basepaired, double-helical structure is preserved, is lacking. That is, fundamental parameters and concepts of CT that may enable prediction and rational design of conductive DNA systems and circuits are greatly needed. Distance dependence and sequence dependence have been investigated in an electrical format by scanning tunneling microscopy (STM). Xu and co-workers41 followed the conductance of double-stranded 8−14mer DNA layers on gold electrodes with STM, finding that the dominant transport mechanism depended on sequence. For G:C-only sequences, CT followed an inverse length dependence, while inclusion of an A:T-bridge within flanking GC segments induced exponentially decaying conductance with an exponential decay factor of β = 0.43 Å−1. Likewise, Dulić et al. observed a 3-fold decrease in conductivity for 12mer sequences in going ́ from 25% to 58% A:T content.43 Alternatively, Kratochvilová and co-workers5 observed very little difference in conductivity between 25% and 50% A:T 32mer sequences. It would assist fundamental understanding of CT and inform design of electronic devices to rationalize these varying trends. Also, to this point, there has yet to be a fundamental study of distance

he construction of nanoscale electronic devices is critical to meet the scaling demands of the semiconductor industry. DNA, the fundamental molecule of life, meets the synthetic and assembly challenges of nanoscale wires.1−24 DNA synthesis is now executed in high yield with automated, highthroughput phosphoramidite synthesis and coupled with chromatography for high purity. Oligonucleotides may be functionalized internally or on either the 3′ or 5′ termini to endow DNA with functionality. Self-assembly may be directed by these modifications or by utilizing the self-organizing capability of DNA base pairing. The order of DNA bases can be sequenced to create arbitrary two- and three-dimensional shapes on the nanoscale.25−28 Double-stranded, fully Watson− Crick base-paired DNA is a well-ordered, closely spaced (3.4 Å) arrangement of conjugated bases, suggesting its use as a bridge for charge transport.21 When utilized in sensing platforms, DNA is unique in that it serves as both the recognition element and the transducer simultaneously, with the ability to distinguish the concentrations and/or activities of proteins and enzymes, the presence of single nucleotide polymorphisms, and the existence of subtle base damage products.1,29−38 Thus, DNA possesses a number of advantages for use in nanoscale electronic applications. The challenge of implementing DNA as a molecular wire lies in obtaining consistent electrical properties, as reports of DNA conductivity have varied from insulating to superconducting.6,11,14−18,38−41 In recent years, it has been established that certain criteria must be met to observe high conductivity: good electronic coupling of the donor and acceptor to the DNA bridge and preservation of the DNA π-stack by maintaining © XXXX American Chemical Society

Received: April 24, 2013 Accepted: August 22, 2013

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dx.doi.org/10.1021/ac401229q | Anal. Chem. XXXX, XXX, XXX−XXX

Analytical Chemistry

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time-of-flight mass spectrometry, and UV−visible spectrophotometry. The DNA films were assembled on chips bearing 16 multiplexed electrodes that permitted interrogation of four sequences on each chip with 4-fold redundancy. The chips were fabricated in a cleanroom environment and UV−ozone treated to remove organic contaminants. This chip arrangement enabled clear comparison between molecular monolayers, as each electrode surface on a given chip was subject to the same processing and cleaning history. The chip system also ensures temperature uniformity across the monolayers, and all results are obtained over averages of multiple monolayers from multiple chip experiments. The DNA monolayers were assembled onto the chips in phosphate buffer (5 mM monobasic/dibasic sodium phosphate at pH 7, 50 mM sodium chloride, 4 mM spermadine) and maintained in buffer throughout electrochemical testing. Electrodes were backfilled with mercaptohexanol to passivate against direct oxygen electrochemistry and remove nonspecifically bound DNA. Chips were subsequently connected to electrochemical testing hardware (CH Instruments CHI750D Electrochemical Analyzer and CHI 684 Multiplexer) via a custom mount. Temperature control was achieved by placing this entire mount in a custom copper enclosure and submerging this conglomerate assembly in a temperature controlled, recirculating water bath (See Supporting Information). Additional details of chip preparation and DNA assembly may be found in our earlier work.33

and sequence dependence of transfer rate in a device format conducive to sensing and practical electronic applications. In this Article, we make use of precision bioconjugate chemistry to investigate charge transport through DNA by means of DNA electrochemistry under physiological conditions. Surface bound DNA monolayers are electrochemically interrogated with a covalently attached redox probe at discrete positions along the sequence, as shown in Figure 1, enabling a

Figure 1. An illustration of the DNA monolayers used in this study. A Nile Blue redox reporter was covalently attached at one of five positions within the DNA to probe distance dependence without changing the intervening sequence. Only one sequence was assembled per electrode.

systematic study of transport with subnanometer precision. This approach allows us to investigate transport at various distances without changing the sequence. We utilize multiplexed chips and kinetic analysis to extract the electron transfer rates and CT yields along the DNA molecular bridge. Furthermore, alternative sequences are used to reveal the principles governing the yield of transport. These measurements are accomplished on a device platform relevant to circuits and sensing. Using these approaches, we distinguish between transport models through study of kinetics and uncover new insight concerning the yield of DNA CT.

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RESULTS AND DISCUSSION Figure 1 illustrates our approach for electrochemical interrogation of the DNA bridge. The double-stranded DNA monolayers were prepared with a 6-carbon alkanethiol linker on the 5′ end of one strand for self-assembly on gold working electrodes. At distinct positions along the complementary strand we covalently coupled a Nile Blue redox probe (see Figure 1 and Supporting Information), a moiety that is electrically conjugated to a modified thymine and reduced upon DNA-mediated CT.30 Thus, the redox probe was in a definite position on the DNA duplex with electronic coupling to the base pair π-stack. Only one sequence was assembled per electrode, but up to four sequences were interrogated simultaneously on the same multiplexed chip (see Supporting Information). The primary AT-rich sequence of this study has been the target of several past DNA electrochemistry experiments in part due to its use in sensing the TATA binding protein.22,30,33 In Figure 2, we show the cyclic voltammetry (CV, 50 mV/s) and square wave voltammetry (SWV, 40 Hz) from our T1 and T17 constructs at room temperature. The CVs and SWVs show distinct redox peaks for both constructs, with T1 considerably larger than T17. These duplexes form monolayers of equal surface coverage as measured by a ruthenium hexamine assay (see Supporting Information). Thus, transport through the DNA bridge to the distal end is considerably less efficient than transport to the bottom-bound probe. The decreased splitting in the T1 forward and reverse CV peaks versus T17 is also indicative of faster kinetics, a feature that contributes to the increased peak height of the SWV signal at this frequency. For clear comparison, CV peak current is used to discuss yields, as SWV signal size is highly sensitive to the choice of frequency. SWV is utilized to extract details of kinetics through the method first described by O’Dea and Osteryoung.44 This

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EXPERIMENTAL SECTION The primary well-matched monolayers used in this study were the 17mer sequences 3′-CTCT4ATATT9TCGT13GCGT17-5′ and the fully complementary sequence 5′-(C6 thiol)-GAGATATAAAGCACGCA-3′ or the sequence 3′-T1TCTATATTTCGTGCGT-5′ and the fully complementary sequence 5′-(C6 thiol)-AAGATATAAAGCACGCA-3′. Tn is the location of the Nile Blue modified thymine, only one of which was present on any given sequence, and C6 thiol is a 6-carbon alkanethiol linker. We use the convention Tn to note each DNA duplex by the position of the probe at base n. The latter sequence pair differs from the former only by the replacement of the 3′-end cytosine with a Nile blue modified thymine on the probe sequence and the corresponding complementary 5′ adenine on the thiolated sequence. The GC-rich sequence 3′-CTGACTGGAGCCTGCGT-5′ coupled to its fully complementary, 5′thiolated sequence was also investigated, where T is the location of a Nile blue-modified thymine. We will note this sequence GC-T17, as it is a GC-rich sequence with a probe at the distal end from the electrode, similar to T17 above. Thiolated sequences were obtained from Integrated DNA Technologies (IDT), while the DNA containing the Nile Blue precursor base was purchased from Trilink and the dye covalently coupled according to established procedures.30,33 These DNA sequences were each doubly purified by high performance liquid chromatography (HPLC) and ethanol precipitated for buffer exchange. The products were characterized by HPLC, matrix assisted laser desorption ionization B



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f1, t (L) ∝ exp( −β ·L)

(2)

where L is the length from donor to acceptor and β is the exponential decay parameter for the overall CT reaction. In short, tunneling gives rise to an exponentially dropping transfer rate with distance. For the distant-dependent transfer rate component due to a hopping mechanism,48 f1,h(L), f1, h (L) ∝ L−η ,

1≤η≤2

(3)

The exponential term η is 1 for a strongly forward-biased hop and 2 for a completely unbiased random walk.48 Thus, for hopping, the transfer rate is inversely proportional to the length of the bridge. Unlike the tunneling mechanism, in which CT is performed in a single step through strongly coupled donor and acceptor wave functions, the hopping mechanism involves occupation of the bridge and is dependent upon the coupling of the individual bridge units.49 Thus, systematic study of the length dependence of the rate of transport should clarify which, if either, of these two mechanisms is dominant in reductive DNA electrochemistry, and this, together with the temperature dependence, will provide insight on the nature of the states involved in transport.

Figure 2. Cyclic voltammetry (CV, 50 mV/s) and square wave voltammetry (SWV, 40 Hz) for T1 and T17 DNA duplexes at room temperature. T1 is located at the base closest to the electrode, and T17 is the distal base. The CV of T17 has been offset by 40 nA for clear comparison.

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EVALUATION OF TRANSPORT MECHANISM To explore the mechanism of CT through these DNA monolayers, we extracted the electron transfer rates k for reduction of monolayers T4, T9, T13, and T17. These four sequences presumably involve transport through the DNA bridge as opposed to direct tunneling between the electrode and redox probe, as is anticipated for T1. In Figure 3A, we plot the natural log of k as a function of probe position for 0 and 30 °C. The data trend is approximated by a line, so we may extract relevant parameters consistent with exponential rate dependence and eq 2 above. The decay parameter β ranges from 0.013 to 0.018 Å−1, in excellent agreement with recent electrical

analysis is more sensitive to redox signals (particularly at low temperature) and more efficient than Laviron analysis45 as parameters are extracted from a single voltammogram. We have recently shown that, when applying this analysis of Osteryoung, we can fit our DNA monolayer SWV curves according to a quasi-reversible first-order electron transfer reaction and extract kinetic parameters.22 Included in our fitting parameters are the standard potential E0, the electron transfer rate k, the electron transfer coefficient α, and the redox active surface coverage Γ*. This latter term can be understood for our system to be the “effective” surface coverage of DNA, a value that can differ from the assembled surface concentration of the monolayer. Our study of the dynamics of k with distance and temperature will be instrumental in distinguishing the dominant transport mechanism, while Γ* will provide further insight on the details of this mechanism.

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MECHANISMS OF TRANSPORT IN ORGANIC SEMICONDUCTORS We seek to establish the distance and temperature dependence of the rate of charge transport through the DNA bridges under electrochemical study. We assume that the charge transfer rate k will depend on distance L and temperature T such that k ∝ f1 (L)f2 (T )

(1)

We measure the overall rate of transfer through the molecular monolayer, which includes processes in addition to DNA CT: tunneling through the alkanethiol linker and CT to/from the redox probe (Figure 1). Thus, our goal of this work is not to establish absolute conductivity but rather to infer the mechanism through the scaling of the rate upon variation of the distance of CT through the DNA bridge. For molecular systems in general, charge transport is accomplished over short distances by tunneling, while multistep hopping dominates for distances beyond a few nanometers.2,8,46,47 These CT mechanisms have distinctive distance dependences of the electron transfer rate. For the distantdependent transfer rate component due to a tunneling mechanism, f1,t(L):

Figure 3. (Upper) The natural log of electron transfer rate as a function of probe distance from the linker (electrode-bound end) of DNA for 0 and 30 °C. (Lower) The electron transfer rate as a function of inverse probe distance from the electrode linker end of the DNA. Transport distances are estimated assuming a 3.4 Å spacing between base pairs. C



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monolayers, respectively. Thus, this shows an approximate trend of increasing activation energy with increasing bridge length. The T1 duplex (not shown) does not show linear behavior on this plot, consistent with the assumption that hopping transport is not needed for its reduction. Thus, it appears from our combined study of distance and temperature dependence that hopping transport plays a dominant role in DNA electrochemistry. Hopping is often found to be the more efficient mechanism in photophysical studies of DNA CT when the distances surpass ∼1 nm, or about 3 base pairs, between donor and acceptor,58−61 as is the case for our T4−T17 constructs. Likewise, tunneling through proteins is typically limited to distances no longer than ≈20 Å.47 (However, care must be taken in assigning mechanisms as alternative processes such as injection-limited currents can influence rate versus distance measurements.62,63) Additionally, for proteins and peptides, hole hopping is facilitated by tryptophan and tyrosine amino acids.64,65 In photophysical studies of DNA, hole hopping is typically understood to proceed spontaneously between guanines due to lower oxidation potentials or endothermically through adenines in the absence of guanines.47,48,66−68 A recent photophysical study66 of length and temperature dependence of hole transfer through DNA for a 16mer construct reported an activation energy (EA = 121 meV) in very close agreement with our T17 monolayer as well as our previous measure22 of the same sequence. This activation energy is smaller than what has been approximated by classical Marcus theory,69 but current efforts to understand the precise quantum mechanical details of inner shell reorganization energy70 may reconcile this difference. A further question arises in the nature of the charge transport in these DNA monolayers: the identity of the charge carrier. To this point, reductive DNA electrochemistry has primarily been understood to involve electron transfer from the electrode to the redox probe. However, given the agreement of our results above with a well-defined hole transporting system,66 the possibility of the Nile Blue probe as a hole donor should be considered. We are currently working on experiments to establish the dominant carrier identity.

measurements of the length dependence of DNA bridging a carbon nanotube gap (β = 0.011 Å−1)50 and estimates of CT through 100mer monolayers (β < 0.050 Å−1).21 This result is in contrast to the rapidly decaying conductance rate found by Xu et al. (β = 0.43 Å−1)41 despite the fact that our sequence is largely AT in content. The difference potentially arises due to the shorter (8−14 base pairs) and thus less stable duplexes used by Xu et al. (see discussion below). Alternatively, our measured range of β values falls within the typical numbers reported for conjugated organic molecular wires, for which β varies from 0.001 to 0.2 Å−1,46,51−57 indicating DNA serves as an effective bridge for CT. Likewise, the extrapolated intercepts, corresponding to no bridge length, are very close to our values of k extracted from the T1 construct. Nonetheless, the coefficients of the determination of the linear fits (R2 values) range from 0.76 to 0.92, indicating that this functional form may not be the best fit of our data. Thus, we should consider applying the hopping mechanism to this data. From eq 3 above, we anticipate k will be inversely proportional to the length of the DNA bridge if hopping transport plays a dominant role. In Figure 3B, we plot k as a function of inverse distance for T4, T9, T13, and T17 monolayers and apply linear fits. This assumes η = 1 for eq 3 above for a highly acceptor-biased walk, consistent with a field-driven process.48 The data follow these fits much more closely than for the exponential plot of Figure 3A. The data are particularly consistent with 1/L dependence for the low temperature (0 °C) points, for which the R2 value of the fit is 0.996. (Using η = 2 yields fits with R2 = 0.949−0.977. This view has merit in consideration of the Debye length.) Thus, the distance dependence of CT rate more strongly points toward inverse distance dependence, suggestive of hopping transport over tunneling transport. Previously, we demonstrated that the T17 monolayer, the monolayer bearing a probe completely distal to the electrode, follows Arrhenius-like behavior over a 0−35 °C temperature range.22 In Figure 4, we plot the natural log of the transfer rate

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YIELDS OF CT A high yield of charge transport through the DNA bridge is foundational to its use as a functional nanowire, so understanding and optimizing yield is critical. Previous studies have shown that the quantum yield of charge transport is independent of rate,66 so we explored its distance dependence independently. In Figure 5A, we plot the yield of probe reduction as measured by the CV peak current versus probe bridge position for the monolayers illustrated in Figure 1. Interestingly, the plot is concave up, with the lowest yield found at the T9 position in the middle of the duplex, with higher yields at either extreme. This is of opposite concavity to the yield versus distance by Lewis and co-workers71 for G-withinpoly-A tracts, where recombination limited transport yields through short distances. This trend is somewhat counterintuitive, considering that the probe for the T9 duplex is considerably closer to the electrode surface than for T13 and T17. This phenomenon cannot be accounted for by kinetics, as the electron transfer rate follows 1/L dependence. Also in Figure 5A, we plot the redox active surface coverage Γ*, showing it to precisely follow the CV peak current trend. Thus, two electrochemical measurements confirm this surprising

Figure 4. The natural log of electron transfer rate as a function of temperature for T4, T9, T13, and T17 DNA monolayers.

versus temperature for T4, T9, T13, and T17 DNA monolayers. All four duplexes exhibit Arrhenius-like behavior, indicative of temperature-activated transport. Thus, we see ⎛E ⎞ f2 (T ) ∝ exp⎜ A ⎟ ⎝ kT ⎠

(4)

where EA is the activation energy for charge transport, kB is the Boltzmann constant, and T is temperature. Following this equation, we extract activation energies of 74 ± 12, 103 ± 28, 144 ± 20, and 125 ± 20 meV for T4, T9, T13, and T17 DNA D



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multiple sequences. Such a correlation of yield with melting temperature has not been reported within the literature of DNA electrochemistry. (Higher conductivity for GC sequences has been noted for hole conductivity in other electrical formats.)5,41,43 The implication for utilizing DNA in nanoscale electronics is clear: to achieve a high yield of charge transport, a DNA bridge of high duplex stability must be used. Along these lines, these results may explain the trends observed in STM literature. The strong sequence dependence of conductivity found by Tao et al.41 and Dulić et al.43 may be rationalized as the sequences investigated were shorter (8−14 bp), exhibiting low melting temperatures and thus very low stability. Alternatively, the minimal impact of sequence on transport ́ observed by Kratochvilová et al. corresponds to 32mer sequences, which are inherently more stable regardless of sequence context.5 Likewise, our correlation of yield with duplex stability can resolve a discrepancy between two electrochemistry reports involving anthroquinone-labeled DNA, with only one showing efficient CT to the probe, in spite of identical probe coupling.42,73 The inefficient construct placed the probe in the middle of the sequence, lowering the melting temperature by 4.5 °C, while the redox-active study had the probe on the distal end, which raised the melting temperature by 4 °C. Finally, direct collision of the redox probe with the electrode surface has been suggested as a mechanism of DNA electrochemistry,74−77 and in one report utilizing singlestranded DNA, 1/L dependence was observed and correlated with results from a flexible chain model.74 A key assumption of that model is that the DNA is much longer than its persistence length. This is a valid assumption for single-stranded DNA but is not valid for our double-stranded constructs, for which persistence lengths have been measured to be approximately 40 nm for buffer conditions similar to ours (sodium and spermidine cations).78 Likewise, the linear increase of CT yield with melting temperature shows that higher signals are obtained when duplexes are less flexible, arguing against direct collision. Furthermore, our β values are consistent with that found from DNA tethered across a planar electrode gap,50 for which direct collision is not possible. These findings, together with our previous study,22 strongly argue that transport occurs through the DNA bridge for monolayers with redox probes tethered away from the electrode-bound end.

Figure 5. (Upper) Cyclic voltammetry peak current (50 mV/s) and redox active surface coverage versus redox probe position for T1, T4, T9, T13, and T17 monolayers at 20 °C. (Lower) DNA melting temperature versus redox probe position for T1, T4, T9, T13, and T17 monolayers at 20 °C.

trend in yields. We can account for this trend by considering the stability of the duplex in each case. Melting temperature characterization with UV−visible spectroscopy (Figure 5B) revealed that the position of the probe changes the melting point by as much as 8 °C. (The UV−visible melting temperature correlates with the stability of the electrochemical signal on the chip; see Supporting Information.) The trend of CV peak current versus distance is clearly correlated with the melting temperature, demonstrating that the yield of CT is tied to the stability of the DNA duplex. If CT yield is generally tied to stability, this trend should hold for other sequences. For this reason, we also investigated sequences of higher and lower melting temperatures. For higher stability, we tested the GC-rich sequence GC-T17 defined in the Experimental Section. This sequence has a substantially higher GC content than the Tn sequences noted above (65% as compared to 41%) and consequently a higher melting temperature (73.0 °C in PO4/spermadine buffer). For lower stability,72 we obtained data from a sequence containing a single CA mismatch, the mismatch-containing analog of T17, labeled MM-T17.22 In Figure 6, we plot the yield of these

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CONCLUSION Overall, our studies of CT rate and yield show DNA is an efficient molecular bridge of charge transport. Concerning rate, the finding of β = 0.013−0.018 Å−1 places DNA among the most efficient conjugated molecular bridges. However, DNA CT rate is better described by an inverse distance dependence which, together with the activation-like behavior, suggests that transport through the DNA bridge is governed by hopping. The trends in CV yields and effective redox-active surface coverages with distance and sequence are rationalized by the stability of the duplex. These results clarify the scaling and stability characteristics of DNA as a molecular bridge, guiding its use in nanoscale electronics and sensing applications.

Figure 6. Cyclic voltammetry peak current (50 mV/s) versus DNA melting temperature for T 9 , T 13 , T 17, MM-T 17 , and GC-T 17 monolayers.

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sequences versus melting temperature along with the T9, T13, and T17 sequences, that is, the sequences with redox probes several bases from the gold working electrode. A linear dependence is noted, with peak current increasing by 0.26 nA/°C and corresponding to a Γ* dependence of 0.52 pmol/ °C. Thus, the proportionality of DNA CT yield to duplex stability as quantified by melting temperature applies to

ASSOCIATED CONTENT

S Supporting Information *

Images of custom temperature controlled electrochemical setup, chemical drawings of the C6 linker and Nile Blue redox probe coupling, illustration of the chip and DNA E



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monolayer layout, melting curves of DNA monolayers, details of simulations for obtaining kinetic parameters, ruthenium hexamine assay for T1, T9, and T17 monolayers, and comparison of T17 and MM-T17 electrochemistry and UV− visible spectroscopy melting characteristics. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Email: [email protected]. Fax: 972-883-2848. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by the National Science Foundation (CMMI-1246762). The authors would like to thank J. Genereux, R. Marcus, J. Barton, M. Hill, Y. Gartstein, and A. Gorodetsky for fruitful discussion.

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