DNA on Stage: Showcasing Oligonucleotides at Surfaces and

PERSPECTIVE pubs.acs.org/JPCL

DNA on Stage: Showcasing Oligonucleotides at Surfaces and Interfaces with Second Harmonic and Vibrational Sum Frequency Generation Stephanie R. Walter and Franz M. Geiger* Department of Chemistry and the Nanoscale Science and Engineering Center, Northwestern University, Evanston, Illinois 60208

ABSTRACT The field of nonlinear optics continues to expand and surprise. The ability to study DNA with nonlinear optics has opened the door to understand, on a molecular level and without the use of external labels, the physical and chemical properties of DNA single and double strands at surfaces and interfaces. In this Perspective, we survey how nonlinear optical probes access the electronic, vibrational, electrostatic, and chiral signatures of interfacial DNA in its native state. We also show how this exciting new field is directly applicable to tracking and understanding molecular recognition in DNA oligonucleotides and aptamers.

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NA plays a fundamental role in the evolution of species and now is emerging as an integral component in the evolution of new technologies. The unique molecular recognition properties of oligonucleotides is exploited in a plethora of medical,1 material,2,3 electronic,4 and photonic5 applications and devices. Despite the tremendous surge of DNA use in science and engineering, surprisingly little is known about the fundamental principles underlying oligonucleotide hybridization ; the key molecular recognition event underlying DNA-based technologies and materials ; in the heterogeneous environments in which oligonucleotide-based devices and materials operate.6 This is not for a lack of trying; experiments in which labeled oligonucleotides are used7-11 have yielded important molecular-level information concerning oligonucleotides in interfacial environments. Label-free probes are available as well for detecting oligonucleotides at surfaces and interfaces.12-15 However, given that most methods for preparing oligonucleotide-functionalized gold and silica surfaces produce 1011 to 1013 strands per cm2,7,15 the applicability of label-free probes for studying oligonucleotide hybridization and duplex melting at interfaces is significantly curtailed by sensitivity limits. Special surface preparation methods for promoting signal transduction or surface-enhanced optical effects have overcome this barrier.16-18 However, these methods either rely on exciting surface plasmons in a fashion that is not molecularly specific, produce spectrally congested data that are difficult to interpret, especially when mixtures of target species are studied in competitive binding assays, or are not quantitative without added standards. Hence, in the context of addressing the demanding performance aspects associated with biodiagnostics, and also from a fundamental science perspective, it is highly desirable to probe oligonucleotide-patterned interfaces in a surface-general and yet chemically specific fashion. Furthermore, studies of DNA at surfaces and interfaces should, in an ideal world, be performed under aqueous flow conditions and in

r 2009 American Chemical Society

real time, quantitatively, with high sensitivity and wide dynamic range, and with direct methods that probe the native system, that is, without the need for external labels. As we will show in this Perspective, these requirements are met by nonlinear optical (NLO) methods. We will describe how nonlinear optics can be used to access the electronic, vibrational, electrostatic, and chiral signatures of interfacial DNA in its native state (Scheme 1) and show how this exciting new field is directly applicable to tracking and understanding molecular recognition in DNA oligonucleotides and aptamers. Note that comprehensive reviews of second harmonic generation (SHG), sum frequency generation (SFG), and the Eisenthal χ(3) method are available elsewhere,19-21 and we will skip right into their applications to DNA.

Nonlinear optics can be used to access the electronic, vibrational, electrostatic, and chiral signatures of interfacial DNA in its native state.

Electronic SHG Spectra of Surface-Bound DNA. The first NLO measurements of DNA focused on quantifying the second harmonic signal intensities based on input power, beam angle and polarization, and concentration of the sample.22,23 Al-Obaidi et al. proved that DNA films composed of short 12-mer adenine- and thymine-based oligonucleotides produced a SHG signal when dried on glass slides. Importantly, Received Date: October 8, 2009 Accepted Date: October 28, 2009 Published on Web Date: November 05, 2009

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DOI: 10.1021/jz9001086 |J. Phys. Chem. Lett. 2010, 1, 9–15


Scheme 1. Nonlinear Optics Allowing for the Probing of Key Spectroscopic and Structural Properties of DNA in Interfacial Environments

it was demonstrated that laser damage did not occur on films irradiated with 1064 nm at energy densities up to 11 mJ/mm2. The polarization of the incident beam appeared to have no effect on the SHG signal, which was attributed to the random orientation of DNA oligomers on the surface. However, the SHG signal intensity was reported to increase with lower incident angles and higher oligonucleotide concentrations.22,23

SHG spectroscopy of DNA-functionalized surfaces and interfaces was a necessary first step toward monitoring molecular recognition events that oligonucleotides undergo at interfaces directly and under aqueous solution.

Figure 1. SHG spectra at the aqueous/fused silica interface of the surface-bound T25/A25 duplex (top trace, filled red circles), surface-bound T25 ssDNA (middle trace, filled blue circles), and NHS linker (bottom trace, filled green circles) with Lorentzian fits. (Reprinted from ref 26. Copyright 2009 American Chemical Society.).

The covalent attachment of single-stranded DNA (ssDNA) on fused silica surfaces models the design of commercially available biosensors, such as those developed by Affymetrix and Agilent.24 Surface immobilization of DNA also eliminates the convolution of surface and bulk processes other than hybridization, such as adsorption and desorption rates of the probe sequences. When choosing single-stranded oligonucleotide sequences, one has many options. Particularly com-

mon among the work reviewed here are adenine and thymine oligonucleotides, which are critical for the separation of mRNA in gene expression profiling applications, such as those commercialized by Invitrogen.25 We expanded on the work by Al-Obaidi et al. by applying resonantly enhanced SHG to characterize AT-containing oligonucleotide-functionalized fused silica lenses.26,27 By scanning the fundamental beam across the two-photon resonance of the π-π* transition of the DNA bases at 260 nm, we obtained the electronic SHG spectra of ssDNA and double-strand DNA (dsDNA) covalently


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attached to fused silica surfaces, as shown in Figure 1. The wavelength of maximal SHG resonance enhancement of both the single and the double strand-functionalized aqueous/ fused silica interface matches that obtained in the bulk (260 nm), while the SHG bandwidth is about two times narrower than what is typical for the bulk aqueous phase. If the linear and nonlinear spectroscopic line shapes report on the molecular environment, then this latter finding could suggest that the π-π* transitions accessed via SHG resonance enhancement sample a different molecular environment from that sampled by bulk UV-vis spectroscopy. This finding is of potential use as an important experimental benchmark for theory calculations of linear and nonlinear electronic transitions of oligonucleotides in various interfacial and bulk environments. In addition, SHG spectroscopy of DNA-functionalized surfaces and interfaces was a necessary first step toward monitoring molecular recognition events that oligonucleotides undergo at interfaces directly and under aqueous solution, which is the broader context of this section. Vibrational SFG Spectra of Surface-Bound DNA. Besides electronic transitions, nonlinear optics is also uniquely sensitive to vibrational resonances, which allows for the characterization of molecular structure. The hybridization efficiency and selectivity of oligonucleotides at interfaces is controlled by molecular orientation, packing density, and electrostatic interactions, all of which control oligonucleotide structure. In addition, the structure of oligonucleotides at surfaces is expected to depend on the sequence composition and length, the linker chemistry, the substrate, the counterions present, the extent of hydration, and the hybridization state of the DNA. Vibrational SFG is exquisitely sensitive to the molecular structure and orientation of adsorbates, which is ideal for the characterization of complex surfaces and interfaces. DNA contains a number of CH oscillators from the methine, methylene, and methyl groups of the sugar backbone and DNA bases, as well as carbonyl and amine groups, which are readily monitored with SFG. Tracking the vibrational fingerprints of DNA monolayers and films with SFG at air/solid and buried liquid/solid interfaces reveals important structural information about surface-localized DNA strands.28-31 To date, SFG has been used to study DNA films at air/solid and aqueous/solid interfaces using silicon,28 gold,29 platinum,30 and silica31 substrates with sequences of various lengths and composition. Furthermore, SFG can be applied to track DNA recognition events in real time and provide molecularly specific kinetic information.

oligonucleotides in air that were chemically linked to platinum substrates.30 DNA monolayers were composed of singlestranded 25-mers, 50 -AGA-TCA-GTG-CGT-CTG-TAC-TAG-CACA-30 , which were modified at the 50 end with HS-(CH2)6, and deposited on Pt(111) with either Tris (tris(hydroxymethyl)aminomethane)/EDTA (ethylenediamine tetraacetic acid) (TE) or KH2PO4/K2HPO4 (PBS) buffer solutions. SFG spectra were recorded with a polarization combination that is uniquely sensitive to the χzzz tensor element in the χ(2) secondorder susceptibility tensor, that is, to anisotropy across the interface. In the CH stretching region (2700-3100 cm-1), the SFG signal contributions from the TE buffer overwhelmed the SFG signal contributions from the ssDNA, whereas the PBS buffer did not contribute to the SFG spectrum. Comparing the spectral features from the thiolated ssDNA monolayer with a monolayer of mercaptohexanol (MCH) indicated that the SFG signals produced by ssDNA films were dominated by the symmetric and asymmetric methylene modes from the aliphatic linker. The absence of SFG signal from DNA suggested that ssDNA is highly disordered, adopting a random orientation at the surface, while the linker is well-ordered.30 Although the majority of single-stranded DNA is expected to exist in a random orientation at the air/solid interface,30,31 the presence of different cations interacting with the negatively charged phosphate backbone can orient the DNA strands.28 Asanuma et al. studied how monovalent and divalent cations impact the SFG spectra of a 20-mer ssDNA and dsDNA sequence covalently bound to silicon (111) surfaces. Due to the low SFG signal intensities produced in their setup, changes in the molecular structure of the oligonucleotides on silicon were indirectly monitored by focusing on the structural changes in the silane linker layer, which was composed of a mixture of silyl-1-decene and silylundecylenic acid coupled to the oligonucleotides.28 Monitoring the ratio of the asymmetric methyl CH stretch intensity to the asymmetric methylene CH stretch intensity of the linker, Asanuma et al. suggested that the presence of divalent cations (Mg2þ and Ca2þ) induces molecular disorder in ssDNA, while monovalent cations (Naþ and Kþ) were reported to increase ordering along the strands. Cations with strong affinities for DNA, such as Mg2þ and Ca2þ, were suggested to cause ssDNA to curve and distort more on the surface than Kþ or Naþ. Upon hybridization, the authors report that divalent cations facilitate duplex formation while monovalent cations induce disorder in the dsDNA strands; however, the extent of disorder was found to be less significant for dsDNA than for ssDNA, which was attributed to the increased rigidity of the double helix when compared to oligonucleotide single strands.28 Koelsch and co-workers studied ssDNA chemically bound to gold substrates via thiol chemistry by analyzing the vibrational SFG response at the air/solid, PBS/solid, and D2O/solid interfaces using a polarization combination that is sensitive to vibrational transition dipole moment components that are oriented perpendicular to the surface.29 The results in the CH stretching region for the short, thiol-modified thymine (T5-SH) and adenine (A5-SH) sequences are shown in Figure 2A and B, respectively. Going from air to PBS buffer and then to D2O reveals spectral changes that are much more

SFG can be applied to track DNA recognition events in real time and provide molecularly specific kinetic information.

We begin by reviewing work on surfaces containing singlestranded DNA. Sartenaer et al. applied SFG to investigate


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structure at the surface. Finally, tuning into the carbonyl stretching region (1680-1760 cm-1), it was confirmed that the structure of the T5-SH oligonucleotide sequence at the D2O/solid interface differs from that at the air/solid interface. The carbonyl stretching region is straightforward to interpret since all spectral features arise only from the DNA bases. On the basis of the carbonyl peak at 1700 cm-1, it was then proposed that the T5-SH strands are tilted in D2O such that the carbonyl groups of the thymine bases are oriented perpendicular to the surface. The vibrational spectra of DNA are very complex and congested due to the multitude of oscillators and the coupling between them. Thus, the assignment of vibrational modes based on SFG alone is difficult. Complementary experiments with ultrafast vibrational pump-probe spectroscopy have investigated adenine and thymine base pairs in solvated environments to confirm coupling interactions32 and to distinguished between N-H stretches on base pairs and O-H stretches from associated water molecules.32 Ultrafast vibrational spectroscopy is sensitive to changes in molecular conformations of DNA and complements structural information obtained by SFG. Combining the two methods will undoubtedly further an understanding of DNA inter- and intramolecular interactions at the molecular level, which is an important future direction of this community. Monitoring DNA Hybridization. The results from the experiments summarized in the previous sections provide a new level of understanding regarding the structure and order of surface-bound DNA strands. Static experiments detailing the electronic and vibrational spectra of interfacial DNA strands have also been complemented with dynamic studies, which enable the monitoring of DNA recognition events directly at surfaces and interfaces. The change in local and supramolecular chirality of DNA single and double strands provides an excellent handle for nonlinear optics to probe, in real time, hybridization interactions and duplex formation. Our group reported the use of polarization-resolved SFG to study the helical conformations of the DNA duplex,31 which sparked further studies that tracked DNA hybridization in situ using SHG.26 The methyl groups on T-tracts hybridized with their complementary A-tracts were investigated with SFG using the pmp polarization combination, which yields information that is similar to that obtained from vibrational linear dichroism. In this experiment, one switches the polarization angle of the plane-polarized upconverting visible beam between plus and minus 45° away from the plane of incidence, as pioneered by Shen and co-workers.33 The chiral nonlinear response of the methyl group, whose C3v symmetry is evidently broken in the environment of a double helix, then illustrated that the rotational sense of direction of the thymine methyl groups in the surface-bound (AT)15 double helix is directly correlated with the antiparallel nature of hybridization.31 These studies showed that SFG is highly sensitive to detecting both the local stereogenic centers along the sugar-phosphate backbone and the macroscopic chirality of the right-handed DNA helix without the need for labels. The sensitivity can be attributed to optical self-heterodyning.26,31

Figure 2. (A) The ssp-polarized SFG spectra of T5-SH on gold in D2O (top trace), PBS (middle trace), and air (bottom trace). The diagram on the right illustrates the brushlike structure of T5-SH on gold. (Reprinted from ref 28. Copyright 2008 American Institute of Physics.) (B) The ssp-polarized SFG spectra of A5-SH on gold in D2O (top trace), PBS (middle trace), and air (bottom trace). (Reprinted from ref 29. Copyright 2008 American Institute of Physics.).

pronounced for the T5-SH strand than for A5-SH strand. This finding suggests that adenine bases associate strongly with the gold surface via nonspecific interactions to lie flat on the surface, limiting the ability of the bases to reorient, in contrast with the binding mechanism of the T5-SH sequence in which the thiol group chemisorbs to the gold surface.29 By monitoring the ratio of the in-plane and out-of-plane asymmetric methyl stretches for thymine at 2968 cm-1 (rip-) and 2954 cm-1 (rop-), the authors suggested that the methyl group on the thymine ring is oriented parallel to the surface in air, PBS buffer, and D2O. Although the rip- to rop- ratio indicated that the orientation of the thymine bases remained essentially constant, the overall spectral features obtained from the T5-SH strands changed dramatically based on the medium above the solid surface, which indicated that the sugar-phosphate backbone is highly susceptible to reordering between air and solution. In D2O, the T5-SH strands were reported to be ordered in a brushlike fashion, as is evident by the high signal intensity of the methylene peak from the sugar backbone at 2880 cm-1. In the presence of PBS buffer, the 2880 cm-1 peak intensity decreases, indicating that the presence of electrolyte decreases electrostatic repulsions between the phosphate groups, allowing for a more flexible


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We also used the nonlinear chiral SHG response of DNA immobilized on fused silica hemispheres to track the surfacebound T25 sequence during hybridization with the complementary A25 strand.26 The results showed that the SHG-LD response was weak when the probe wavelength was tuned away from two-photon resonance of the π-π* transition of the nucleobases at 260 nm or when ssDNA was probed. However, when the incident beam was tuned to be in twophoton resonance with the π-π* transition of the nucleobases, the SHG-LD response of the DNA-functionalized surfaces was found to increase as soon as the complementary sequence was added to the static reaction cell. Hybridization was found to be complete after approximately two hours. Upon hybridization, the surface bound DNA is expected to result in a rigid and stable right-handed double helix. Our previous SFG work showed that DNA hybridization also induces ordering of the nucleobases, as is evident by the clear appearance of the thymine methyl symmetric (2875 cm-1) and asymmetric (2950 cm-1) stretches in vibrational SFG spectra that probe the components of the vibrational transition moments oriented along the surface normal.31 The ordered double helix that is formed when oligonucleotidefunctionalized surfaces interact with their complementary strands then results in exciton coupling, which gives rise to the strong SHG-LD response that is probed when using resonance enhancement in the SHG-LD experiments.26 Just like in our vibrational SFG work, the sensitivity of this SHG-LD experiment can be attributed to optical self-heterodyning.26,31 Since the sugar-phosphate backbone on DNA remains the same between sequences, being able to differentiate the characteristic vibrational signatures of the DNA bases is an important step in tracking hybridization. To this end, we exploited the tensorial properties of vibrational SFG to study fused silica windows functionalized with a 20-mer adenine sequence (A20) that was then hybridized with its complementary T20 strand following the procedures of Boman et al.26 The A20 sequence does not contain any methyl groups. We therefore expect the methyl symmetric and asymmetric modes to appear in the SFG spectra as hybridization to the complementary T20 sequence occurs. The two spectra displayed in Figure 3A show that the ppp polarization combination, which accesses the χzzz tensor element in the χ(2) second-order susceptibility tensor, is highly sensitive to the anisotropy within the array of methyl groups that is set up across the interface when the helical duplex is formed. Provided that the helix is oriented mainly along the surface normal, the methyl asymmetric CH stretches line up along the surface normal and thus give rise to the strong ppp polarization response in the SFG spectrum. In contrast, Figure 3B shows that this anisotropy of the helical array of methyl groups is not picked up by the ssp polarization, which is not sensitive to the χzzz tensor element. Instead, the ssp-polarized SFG spectrum is most likely dominated by the presence of the aliphatic silane linker, similar to what was reported by Sartenaer et al.30 These results are promising and are now being pursued at the aqueous/solid interface to monitor the signal intensity at 2960 cm-1 and track hybridization in situ. Quantification of DNA on Surfaces and Interfaces. Along with monitoring the structure of DNA single and double strands at


Figure 3. Vibrational SFG spectra of A20 ssDNA (bottom blue trace) and the A20:T20 complementary duplex (top red trace) recorded at the air/fused silica interface using the ppp (A) and ssp (B) polarization combination. Spectra are offset for clarity. The large signal intensity increase from the methyl asymmetric stretch at 2960 cm-1 recorded using the ppp polarization combination distinguishes between the single-strand DNA and the complementary double strand.

surfaces and interfaces, nonlinear optics have also been applied to quantify the charge density and, subsequently, the strand density of oligonucleotides on surfaces.26 These experiments are carried out as follows. The negatively charged DNA strands set up an interfacial potential and provide an electrostatic handle for studying the strand density of DNA with the Eisenthal χ(3) technique.21,26 The molecular origin of the Eisenthal χ(3) response can be attributed to the alignment of water dipoles within the electric double layer set up at a charged aqueous/solid interface.21 In the Eisenthal χ(3) method, one integrates over the entire second- and thirdorder nonlinear susceptibilities of the interface, the water molecules, and the counterions within the electrical double layer. The restructuring of water molecules in the presence of DNA was demonstrated by Wurpel et al. at the D2O/charged lipid/air interface using SFG.34 In this case, a cationic lipid monolayer aligns water molecules at the air/D2O interface, which reorient as increasing concentrations of negatively charged λ-phage DNA are added to the solution. Figure 4 shows that the SFG signal intensity of D2O in the OD stretching region decreases rapidly as DNA is added. Notably, as the water molecules reorient, a monolayer of water was reported to remain trapped between the cationic lipid and DNA layer, contributing to the increase of the broad peak at 2700 cm-1.34

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The inset in Figure 5 illustrates that the strand density does not vary significantly with nucleotide length. The fact that the number of oligonucleotide strands probed within the 30 μm focal spot of our laser corresponds to about 6 attomoles of DNA demonstrates the exquisite sensitivity of nonlinear optics to study DNA at interfaces. Nonlinear optical studies of DNA are now being carried out worldwide. The field has rapidly evolved over the past 10 years and will certainly address many exciting new scientific questions regarding DNA-target interactions in the future. This Perspective has hopefully helped to summarize the current state of the field and to inspire new research directions for applying nonlinear optics to DNA in a variety of environments. Specifically, we foresee important application developments for imaging DNA-patterned chips used in biodiagnostics, which are attainable through nonlinear optical imaging and multiplexed signal detection. By circumventing the need for resonance energy transfer approaches, which require the use of ever more sophisticated molecular labels with the appropriate optical and chemical properties, nonlinear optical imaging is poised to become an important new player in the arena of probing biomolecular interactions. In addition, the unique structural sensitivity and coherent nature of nonlinear optical methods will allow for vast improvements in sensitivity via heterodyne detection and chemical specificity via access to any vibrational resonances, molecular and supramolecular chirality, and electronic properties. Improvements in these areas represent the next frontier, which will open up the field for chemical imaging of DNA-target interactions at interfaces. Finally, biopolymers originating from biodegradation processes are important in geochemical environments, where they can partition to liquid/solid interfaces and sequester metal ions and small molecules whose bioavailability or toxicity are key environmental concerns. The tremendous success of nonlinear optical methods for studying DNA at surfaces and interfaces will undoubtedly create a foundation for quantifying molecular interaction in the biogeochemical arena as well.

Figure 4. SFG spectra and fits of the cationic lipid/D2O interface in the presence of increasing concentrations of λ-DNA. (Reprinted from ref 34. Copyright 2007 American Chemical Society.).

Figure 5. Interfacial charge density and oligonucleotide strand density (inset) as a function of oligonucleotide length.26

We recently applied the Eisenthal χ(3) technique to quantify thermodynamic information for DNA-functionalized fused silica surfaces, including the interfacial charge density, the interfacial potential, and the change in the interfacial energy density for ssDNA under low and high salt conditions.27 We calculated the charge densities for oligonucleotides containing 15, 25, 30, and 35 thymine nucleotides from charge screening experiments (see Figure 5).26 In these experiments, the interfacial charges from the phosphate groups on the surface-bound oligonucleotide single strands orient the water molecules within the electrical double layer. Increasing amounts of salt then screen out the charges, resulting in a decrease of the interfacial potential. The SHG χ(3) signal tracks the third-order response of the water molecules, and charge densities are obtained using electric double-layer models such as the Gouy-ChapmanStern model.26 In Figure 5, the interfacial charge density is plotted against the number of nucleotides, and a slope of 1.1(2) charges per nucleotide is obtained. This result is expected given that each nucleotide contains one negatively charged phosphate group. The number density of surface-bound DNA was then calculated from the interfacial charge density, the elemental charge, and the nucleotide length and was found to be around 5 1011 strands/cm2 for fused silica surfaces.26


Nonlinear optical imaging is poised to become an important new player in the arena of probing biomolecular interactions. AUTHOR INFORMATION Corresponding Author: *To

whom correspondence should be addressed. E-mail: geigerf@ chem.northwestern.edu. Fax: USþ847-491-7713.

Biographies Stephanie Walter, a graduate of Saint Lawrence University, is pursuing her chemistry Ph.D. at Northwestern University, working with professor Franz Geiger, who began his independent career in 2001 after a Postdoc with Mario Molina and a Ph.D. with Janice

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Hicks. Please use the following URL to visit the Geiger group Webpage: http://chemgroups.northwestern.edu/geiger/new_page/ GEIGER_LABS/Welcome.html.

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ACKNOWLEDGMENT This work was supported by the Northwestern

University Nanoscale Science and Engineering Center (NSEC). S.R.W. acknowledges a William Balanoff fellowship. F.M.G. acknowledges the NSF Experimental Physical Chemistry CAREER program (Grant No. CHE-0348873) and an Alfred P. Sloan Foundation fellowship.

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DNA on Stage: Showcasing Oligonucleotides at Surfaces and

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