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Molecular Dynamics Simulations of the Adsorption and Dynamical Behavior of Single DNA Components on TiO2 Susanna Monti*,† and Tiffany R. Walsh‡ † ‡
CNR-Institute of Chemistry of Organometallic Compounds, Area della Ricerca, via G. Moruzzi 1, I-56124 Pisa, Italy Department of Chemistry and Centre for Scientific Computing, University of Warwick, Coventry, CV4 7AL, United Kingdom ABSTRACT: The adsorption of the four DNA bases (adenine, guanine, thymine, and cytosine) on a mineral surface (titanium dioxide) is studied through classical molecular dynamics simulations and potential of mean constrained force calculations to give a reliable description of their binding behavior, identify the best binding arrangement, and quantify the strength of their interactions with the inorganic surface. Several configurations are identified, and the analysis of the data has revealed that the general tendency is to adsorb on structured solvent layers, which are in direct contact with the substrate. In this region, the molecules are perpendicular to the slab most of the time, do not adopt a preferential orientation, and explore different areas of the interposing water layers. Frequent escape into the bulk solvent is observed, suggesting that the interactions between the bases and the solvent layers are not strong enough to keep the molecule close to the surface.
’ INTRODUCTION The investigation of covalent immobilization or direct deposition of oligonucleotides on substrates is one of the first steps in DNA microarray design.1,2 These devices, which are based on DNA recognition/capture events between unknown target singlestranded DNA sequences present in solution and tethered probes located on a substrate, are used as genosensors in a variety of different fields, including genetics, medicine, and drug discovery.3 6 The growing interest in developing more efficient and highly tuned genosensors is related to the ability of these systems to perform massive parallel sequence analysis and selective identification which could be applied to disclose genetic diseases and infection agents.7 14 Experimental and theoretical studies demonstrated that an appropriate choice of the substrate is strategically important to achieve efficient sensing systems with strong signal intensities and a proper dynamic range of action.15 27 Metals such as gold, silver, silicon, and tin and metal oxides such as SiO2, SnO, In2O3, and TiO2 are known to be appropriate supporting media for oligonucleotide probe attachment, but the use of metal oxides was more advantageous especially when the hybridization signal was detected through electrical measurements, as an alternative to fluorescence reading, due to the excellent adherence properties of the oxides, their chemical stability, good electrical conductivity, and optical transparency.28 32 Zapol and co-workers reported that TiO2 oligonucleotide nanocomposites were able to hybridize with the complementary strands, were very stable, did not agglomerate, and could withstand incubation at high temperature.33,34 However, surface r 2011 American Chemical Society
characteristics and interfacial interactions could severely change the electronic properties of both the molecule and the substrate, critically affecting the performance of the final devices.35 Indeed, depending on the reactivity of the substrate, it is sometimes convenient or even necessary to preadsorb passivating layers, such as metal atoms or organic molecules, directly on the interface to prevent surface contamination during deposition of the oligonucleotides, improve nanopatterning, and promote the formation of stable supramolecular structures.36 41 In this context, tailored molecular dynamics simulations are very useful because they can give important insights into interfacial properties at the atomic resolution.42 52 In particular, the evaluation of both the dynamics and binding characteristics of single oligonucleotide components near the surface could help to disambiguate and suggest possible effects that water, ions, and surface topology might have on DNA hybridization or on its adsorption onto such an inorganic layer.53 Binding properties of the four nucleotide bases, namely, adenine (ADE or A), thymine (THY or T), guanine (GUA or G), and cytosine (CYT or C) (Figure 1), to the rutile (110) surface in aqueous solution are explored through classical molecular dynamics simulations in conjunction with potential of mean force (PMF) calculations, which are used to determine their free energy change upon adsorption as a function of distance from the titanium oxide layer. The preliminary estimates of the relative Received: August 18, 2011 Revised: October 20, 2011 Published: October 24, 2011 24238
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Figure 1. Stick representation of four DNA bases.
adsorption free energies of DNA bases, reported in this work, and their characteristic way of binding could give a possible picture of the various interactions which could take place at the interface when a long DNA chain reaches the surface.
’ COMPUTATIONAL DETAILS: MODELS AND SIMULATION PROTOCOLS In agreement with previous investigations,47 50 the rutile (110) surface was chosen as a model system because it is the most stable crystal face where the main relaxation is perpendicular to the layer, and at room temperature this readaptation is minimal. The geometry of the inorganic substrate consisted of a five-layer slab with dimensions of about 37 35 Å2 in the xy-plane. Periodicity was applied in all directions (x, y, and z), but the size of the simulation box along z was extended to 104 Å to ensure the ionic strength of the solution in the simulation cell was reasonable. About 4050 water molecules were added between the slab and its periodic image in the z-direction, and the density of the system was equilibrated such that the central region of the interslab water reproduced the experimental bulk value, by means of a series of energy minimizations and constant volume, constant temperature MD runs. Temperature was maintained at 298 K using the Nose Hoover thermostat.54,55 A negatively charged partially hydroxylated surface, roughly corresponding to physiological pH (pH of 7 8),56,57 was obtained by adding nine terminal hydroxyl groups to selected 5-fold-coordinated Ti atoms on both of the faces in contact with solvent molecules (18 OH groups in all). Following the procedure used by Predota and co-workers,58 these sites were chosen in such a way that the Coulombic repulsion between them was minimal. All the surface atoms were fixed at the crystal geometry, except for the terminal hydroxyl groups, which were kept flexible and could rotate throughout the simulations. The negative surface charge was counterbalanced by adding to the solution twelve Ca2+ and six Cl ions, which compensated the total negative charge of the slab ( 0.104 C/m2). Long-range electrostatic interactions were treated with the particle mesh Ewald (PME) method,59,60 while the short-range interactions were truncated at 12 Å. The equations of motion were integrated using a time step of 1 fs, and the configurations were saved every 1000 steps (1 ps). All simulations were performed with the GROMACS 4.0.7 code.61 The hybrid assembly was described using a tuned combination of force fields which had been already tested in previous works.43,47 The AMBER force field was used for the DNA bases,
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the modified TIP3P force field62,63 for water, and the force field reported by Predota et al.58 for rutile (110). The free energy adsorption profiles for the four nucleotides were calculated using the potential of mean constraint force (PMF) approach choosing as a reaction coordinate the distance from the center of mass of the base and the titania interface.44,47,64 Even though the center of mass of each molecule was constrained at different separations from the top layer of the slab (fixed z coordinate), the base could move freely in the x y plane (plane parallel to the interface) and explore different areas of the rutile (110) layer. The bulk region of the solvent (about 20 Å from the surface) was chosen as the zero for the integration, and the error of the constraint force was calculated by means of the block-averaging method available in GROMACS.65 About 30 z positions were considered for each nucleotide, and the whole configurational space was sampled, through constrained MD simulations, for about 100 ns (3.5 ns per position, and the first 0.5 ns was used for equilibration). Starting from the identified surface-binding arrangements, a series of 20 ns molecular dynamics (MD) simulations were carried out to explore motion and adsorption characteristics of these molecules when they could move freely in solution.
’ RESULTS AND DISCUSSION Negatively Charged Surface Model: Water and Ions Dynamics. As a first check, the adsorption properties of water,
calcium, and chloride ions were investigated in detail analyzing their density profiles as a function of the z coordinate. From preliminary tests, it was observed that the structure of water was unaffected by the presence of the ions and was essentially due to the charged nature of the interface in agreement with the results of Predota and co-workers. As can be noticed in Figure 2, where the density plots obtained from the four unrestrained MD simulations are depicted, three distinct peaks characterize the trend of water adsorption. These are located at about 2.7, 3.6, and 5.4 Å from the top layer of the slab. The highest water density corresponds to those molecules which occupy the sites above the undercoordinated titanium atoms and also located at hydrogen bond distance from the outof-plane oxygens of the surface. The second and third peaks represent, instead, those waters which are coordinated to these two mixed layers. Beyond the third peak, water structuring adopts the properties of the bulk solvent. The overall trend of the water density profile, which is identical in the four cases, suggests that to be inserted into the different solvation regions of the slab a water molecule requires thermal activation because of the existence of successive energy barriers along its approaching path toward the substrate. However, being sufficiently high, these barriers perform also the function of preventing the adsorbed waters from escaping to the bulk.47 Although the first water layer seemed to be placed at slightly longer distances in comparison with the corresponding film adsorbed on the nonhydroxylated neutral surface, the general behavior of the adsorbed water was quite similar in the two models. As far as cations are concerned, these were chosen on the basis of experimental findings and previous theoretical studies66 69 which indicated that calcium ions could perform the function of linking agents by acting as a bridge between the decorating molecule and titania. According to Reviakine and co-workers, specific effects mediated by Ca2+ ions were most likely responsible for the 24239
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Figure 2. Water, ions, and base densities as a function of the z coordinate calculated from the unrestrained MD simualtions.
enhanced protein and lipid adsorption on TiO2 and regulated the lateral mobility of these molecules.67,68 In the present study, Ca2+ ions were found adsorbed on top of one or between two terminal oxygens of the surface and appeared to be strongly bound to the interfacial region but largely excluded from the very first solvation layer (Figure 2). No calcium ions fluctuated freely in solution, but all of them were practically locked to their positions after adsorption. These results, together with earlier experimental and theoretical observations, indicate that Ca2+ ions have the tendency to become an integral part of the interface. As confirmed by Ca2+ density profiles, the ions were prevalently located between the first two hydration layers, preferred binding out-of-plane oxygens, and were only partially surrounded by solvent molecules. In agreement with data reported in the literature,66,70,71 both monodentate and bidentate types adsorption were predicted. Deeper inspection of the various locations of the ions indicated that, at the surface charge density considered in this study, the most probable binding mode of the cations is the one where they are surrounded by a terminal oxygen and five water molecules at an average distance of about 2.2 Å. Bidentate arrangements were rarely observed, whereas complexes between calcium and the Ti OH surface sites were frequently formed. The analysis also suggests that the dehydration and distortion of the primary hydration shell, which accompany the adsorption of cations, take place in close proximity to the surface. Persistent interactions with chloride ions were also noticed. Indeed, these anions happened to be in the first coordination sphere of the cations at an average distance of 2.5 Å. Although, in principle, anions should be found far from negatively charged substrates, the results of these investigations showed, in line with other studies,58,70 that chloride ions could reach the surface and even adsorb on specific sites when multivalent cations are present.
Indeed, closer inspection of the sampled configurations revealed that Cl had direct interactions with Ca2+ being inserted in their first coordination sphere, and as a consequence, they were kept close to the surface at average distances in the range 3.2 4.5 Å (Figure 2, green lines). The position of the peaks visible in Figure 2 is clearly related to the specific location adopted by chlorides in the coordination sphere of calcium: the small peak describes a lateral orientation (which sees the anion closer to the surface), whereas the highest peak indicates on top positions, that is, vertical alignments in the z direction (longer distances from the surface). As can be noticed, the distribution of lateral arrangements covers only half the number of anions inserted in the simulation box thus supporting the view of a certain degree of repulsion and a quite low affinity of these ions toward the titania layer. Base Adsorption, Location, and Dynamics. Before commenting on the data on base adsorption, it is worthwhile to point out that both the size and the rigidity of the molecules prevented their adsorption in a flat orientation between the rails formed by the bridging oxygen atoms protruding from the rutile (110) surface along the [001] vector. Indeed, as already observed for benzene,47 the spacing between the rails was not sufficiently wide (about 6.2 Å) to host binding arrangements other than those from tilted orientations. However, even though tilted orientations could, in principle, facilitate the insertion of the base more deeply at the aqueous slab interface, a stable adsorption mode could be reached only if the different groups of the molecule were able to find a position where surface repulsion was minimal. Considering the heterogeneous nature of the rings, the topology of the surface, and the presence of strongly adsorbed solvent species, the bases were hardly able to achieve the delicate balance between repulsive and attractive interactions, and thus in the unrestrained dynamic description very specific adsorption modes could not be identified. 24240
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Figure 3. Adsorption free energy (PMF approach) of ADE on charged partially hydroxylated rutile (110) in solution as a function of the distance between the ADE center of mass and the top layer of the titania slab. The adsorption geometries corresponding to the most probable arrangements adopted by the molecule in the minima of the curves are displayed on both sides of the graph. Calcium and chlorine ions are represented by orange and green spheres. The structured water layer is depicted by means of thicker sticks. OH hydrogens are undisplayed for clarity.
Figure 4. Adsorption free energy (PMF approach) of GUA on charged partially hydroxylated rutile (110) in solution as a function of the distance between the GUA center of mass and the top layer of the titania slab. The adsorption geometries corresponding to the most probable arrangements adopted by the molecule in the minima of the curves are displayed on both sides of the graph. Calcium and chlorine ions are represented by orange and green spheres. The structured water layer is depicted by means of thicker sticks. OH hydrogens are undisplayed for clarity.
Adsorption Free Energy Profile. First Steps toward the Surface. The trend of the adsorption free energy of the bases along their approaching path toward the top layer of the titania slab is displayed in Figures 3 6 together with the characteristic adsorption geometries corresponding to the minima of the curves. Monoand bidimensional density profiles, calculated from the 20 ns unrestrained MD simulations, are also shown in two separate figures (Figures 2 and 7) to give a more complete description of the base adsorption scheme when it could move freely in solution. As it appears from the examination of the PMF plots, as the bases got closer to the surface, they reached a region located at the boundary between the structured waters and the bulk (Figure Figure 2), at about 6.9 ( 0.1 Å from the top plane of the slab, where they could be comfortably accommodated. This region was explored quite frequently during the unrestrained dynamics implying that, at T = 298 K, the structured solvent layer covering the surface could have a significant impact on the adsorption of incoming foreign molecules, preventing them from quickly establishing direct contacts with the titania substrate in the case
of ADE adsorption or establishing direct contact at all for the other adsorbates (vide infra). These findings are in line with other observations on peptide adsorption which turned out to be mediated by the first water layer.43 Examination of the restrained motion in that region revealed that the base rings frequently changed their inclination relative to the surface and engaged hydrogen bond interactions with the adsorbed waters through their donor and acceptor groups. Base Location during Adsorption on the Outer Water Layer. To quantify the frequency of these tilting movements, in terms of preferential binding affinity, the distance distributions of a couple of atoms of each base (chosen such that these atoms are located on opposite sides of the rings) from the surface were analyzed and compared (Figure 8). N6 and N9, O2 and N1, O6 and N2, and N4 and O2 were chosen for ADE, THY, GUA, and CYT, respectively (atom labels are displayed in Figure 1). It should be noted that these separations could be remarkably different from the characteristic distance identifying the PMF 24241
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Figure 5. Adsorption free energy (PMF approach) of CYT on charged partially hydroxylated rutile (110) in solution as a function of the distance between the CYT center of mass and the top layer of the titania slab. The adsorption geometries corresponding to the most probable arrangements adopted by the molecule in the minima of the curves are displayed on both sides of the graph. Calcium and chlorine ions are represented by orange and green spheres. The structured water layer is depicted by means of thicker sticks. OH hydrogens are undisplayed for clarity.
Figure 6. Adsorption free energy (PMF approach) of THY on charged partially hydroxylated rutile (110) in solution as a function of the distance between the THY center of mass and the top layer of the titania slab. The adsorption geometries corresponding to the most probable arrangements adopted by the molecule in the minima of the curves are displayed on both sides of the graph. Calcium and chlorine ions are represented by orange and green spheres. The structured water layer is depicted by means of thicker sticks. OH hydrogens are undisplayed for clarity.
minima (surface-center of mass of the molecule), and single atoms could be found closer to the interface. As it can be observed in Figure 8, the most probable location of the carbonyl oxygen close to the surface is at a separation of about 5.6 Å and seems the preferred arrangement adopted by GUA and CYT, which, instead, had their NH2 groups farther away from the layer (at about 8 and 6.6 Å, respectively). Even though in the case of THY the closest peak positions agree with those showed by CYT, a higher peak centered at about 7.2 Å appears in the oxygen distance profile, suggesting that the closeness of all the groups makes it difficult to identify a definite binding characteristic which could be obtained, instead, as a combination of the different equally probable orientations. As far as ADE is concerned, both the shape of the distribution and the shift of the peaks support the view of a more frequent interchange between the two different inclinations which took the two sides of the ring to face the adsorbed water layer. However, the closest distance was reached by the NH2 group (6.0 Å from the titania layer). Summarizing the results and inspecting several representative snapshots of the minima, it could be deduced that: (1) the most probable binding configurations were characterized by an inclined
orientation of the base rings with respect to the substrate and (2) the bases were very mobile, and even if most of the time they adopted an almost vertical arrangement they frequently changed the side exposed to the bulk solvent, as confirmed by the broad distributions of the angle between the base ring and the interface. These findings suggest that the orientation of the molecule in close proximity to the titania slab was biased only slightly by the influence of the substrate, and a continuous rotational translational motion or tumbling of the adsorbates could take place. Base adsorption trends in the distance range 6.5 9.0 Å are all very similar to each other, and the long-distance minima are characterized by a weak favorable binding energy in the range 1.6 4.6 kJ/ mol which substantially describes the adsorption of the bases on the structured solvent layer. Adsorption Free Energy Profile. Over the Barrier toward the Surface. As the molecules moved toward the surface from the outer minimum, they encountered a barrier which separated the first from the second minimum visible in the PMF plots. The barrier height is around 3, 10, 11, and 18 kJ mol 1 for ADE, GUA, THY, and CYT, respectively, suggesting that the DNA bases required thermal energy to get over the barrier and reach the surface. 24242
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Figure 7. Two-dimensional density maps. In the background the frozen substrate is rendered by means of colored balls (titanium = gray, oxygen = red, hydrogen = light blue). The position of the OH groups is highlighted by white crosses. The position of the molecules is depicted by means of violet/blue areas, whereas Ca2+ and Cl ions are identified by yellow and green patches.
Their closest accommodation distance, which corresponds to the second minimum in the free energy adsorption profiles, is found at about 4.9, 5.1, 5.1, and 4.4 Å for ADE, GUA, THY, and CYT, respectively. All the “short-distance” minima, except ADE which had a very favorable binding energy of about 15 kJ/mol, correspond to a less advantageous adsorption with respect to the previous positions. However, the molecules were not trapped inside those regions but could easily escape thanks to the smaller barriers (6, 8, and 3 kJ/mol for GUA, THY, and CYT, respectively) which separated those sites from locations farther away from the surface. Instead, the behavior of ADE appears totally different: a preference for this base emerges from the PMF profile and can also be deduced from the more limited region explored by the molecule during its unrestrained motion in solution (Figure 3). The most probable location of the base turned out to be in close proximity to the surface, and its groups were inserted in the very first solvation layer directly adsorbed on the slab. In all the other cases, the molecules appeared to adopt more frequently specific orientations where the carbonyl oxygen pointed toward the interface (Figures 4 6). Notwithstanding this, the atom was not able to form monodentate coordinations with any of the 5-coordinated basal Ti atoms or be involved in other strong interactions with the surface atoms because of the presence of the nearby NH moieties which mitigated and weakened its binding. The molecules hardly found a better arrangement but only maintained a balanced position essentially driven by the carbonyl motion. A more relaxed stable arrangement was observed, instead, in the case of ADE. The NH2 group pointed toward the bulk of the solvent, whereas the opposite side of the ring was hydrogen bonded to the out-of-plane oxygens and OH groups of the slab. It should be noticed that all the configurations extracted from the restrained simulations in the “short-distance” regions are
Figure 8. Atom-surface distance distributions in the minima of the PMF plots belonging to the “long-distance” region. Atom labels are displayed in Figure 1.
characterized by a position of the “ligand” which could be reached only if some of the adsorbed solvent molecules are displaced from their favorable binding sites. The adsorbate can remain between the rails of the surface bridging oxygens inside the first two water layers but cannot coordinate directly its groups with the surface Ti atoms. Moreover, it mobility seems limited and biased by the surrounded species. Molecular Electrostatic Potential of the Bases and Their Permanence Near the Surface. Inspection and comparison of the characteristic features of the molecular electrostatic potential 24243
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Figure 9. Molecular electrostatic potential of ADE, GUA, CYT, and THY on the solvent accessible surface. Positive regions (blue), negative regions (red).
(MEP) of the bases are useful to further explain their behavior when close to the surface and could be used to identify the most probable interaction sites which drive the bases toward specific regions on the partially hydroxylated rutile (110) face. In Figure 9 the solvent accessible surface of the molecules is colored according to the value of the MEP. Intense blue, vivid red, and white represent high positively charged regions, high negatively charged regions, and zero potential regions, whereas lighter colors indicate lower MEP values. All of the molecules, except CYT, which displays a strong dipolar character, show a rather inhomogeneous charge distribution (responsible for an effective quadrupole moment greater than that for cytosine which is consistent with a significant negative charge accumulation at the oxygen atoms of the carbonyl units and a distinct negatively charge depletion at the neighboring protonated nitrogens, which favors an electrostatic interaction
Figure 10. Evolution of the base-surface distance (center of mass of the base) during 10 ns (from t = 5 ns to t = 20 ns) of the unrestrained MD runs.
between these portions of the bases and the oxygen sites of the surface). This interaction is stabilized best, and thus maximized, when the molecules are perpendicular to the interface and point the positive moieties toward the layer. However, the presence of counterions and water molecules, stably and strongly adsorbed on the interface, mitigates the overall negative potential and, in a certain sense, extends the adsorption layer to farther distances. As a consequence, the base’s responsiveness to the surface influence is not fixed and unchanging but highly dynamic. The contiguous traits with alternate positive and negative potential, displayed in Figure 9, are recognized and attracted by the complementary regions on the surface. However, the larger extension of surface zones with the same negative or positive potential causes 24244
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’ CONCLUSIONS Molecular dynamics simulations were carried out to explore the configurational landscape of the adsorption of single DNA nucleotides on rutile (110). All the bases showed the tendency to settle in the region close to the surface just outside the structured solvent layer in contact with the slab. Indeed, stable arrangements were mediated by the solvent, and the orientation of the base rings was most of the time perpendicular to the surface, that is such as to maximize the number of hydrogen bonds and to minimize unfavorable interactions. This kind of binding was not strong enough, and migration of the base into the solvent was very frequently observed. To understand if other possible binding locations, closer to the surface but inaccessible because of the existence of energy barriers, could be present, potential of mean constrained force techniques in combination with MD simulations were performed. The free energy change upon adsorption was calculated, and several binding configurations were identified. However, most of these structures (in the case of GUA, CYT, THY) had unfavorable free energy of binding mainly due to repulsive interactions between oxygen moieties. Therefore, the molecules could adopt unrealistic orientations hindered when the restraints were released. The results suggest that a low dipolar character (ADE) favors direct binding to the surface, whereas a higher dipolar character and lower effective quadrupole moment are responsible for reduced affinity for the layer and greater mobility (CYT). However, it is worth noticing that, although the original idea was to describe and explain the behavior of the bases on a charged partially hydroxylated surface, the neutralizing effect due to the counterions modified both the pH condition and the surface structure, making it very similar to a neutral substrate. This effect was essentially due to the migration of the added counterions, from the bulk solvent to the surface and their residence there throughout each entire simulation. Our findings are reliant on our chosen force field providing a physically reasonable description of the interface. Further experimental studies of these types of systems will be invaluable in advancing the validation process for these force fields. ’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
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’ ACKNOWLEDGMENT The authors gratefully acknowledge the computing facilities of CINECA (ISCRA project, Bologna, Italy) and the CSC at the University of Warwick. ’ REFERENCES (1) Pirrung, M. C. Angew. Chem., Int. Ed. 2002, 41, 1276. (2) Heller, M. J. Annu. Rev. Biomed. Reg. 2002, 4, 129. (3) Storhoff, J. J.; Mirkin, C. A. Chem. Rev. 1999, 99, 1849. (4) Graves, D. J. Trends Biotechnol. 1999, 17, 127. (5) Schena, M.; Heller, R. A.; Theriault, T. P.; Konrad, K.; Lachenmeier, E.; Davis, R. W. Trends Biotechnol. 1998, 16, 301. (6) Alon, U.; Barkai, N.; Notterman, D. A.; Gish, K.; Ybarra, S.; Mack, D.; Levine, A. D. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9212. (7) Bansal, A.; Lewis, N. S. J. Phys. Chem. B 1998, 102, 4058–4060. (8) Song, J. H.; Sailor, M. J. Comments Inorg. Chem. 1999, 21, 69–84. (9) Patolsky, F.; Lieber, C. M. Mater. Today 2005, 8, 20–28. (10) Park, S. J.; Taton, T. A.; Mirkin, C. A. Science 2002, 295, 1503–1506. (11) Webb, L. J.; Lewis, N. S. J. Phys. Chem. B 2003, 107, 5404–5412. (12) Ziegler, C. Anal. Bioanal. Chem. 2004, 379, 946–959. (13) Lasseter, T. L.; Cai, W.; Hamers, R. J. Analyst 2004, 129, 3–8. (14) Jane, A.; Dronov, R.; Hodges, A.; Voelcker, N. H. Trends Biotechnol. 2009, 27, 230–239. (15) Kane, D.; Jatkoe, T. A.; Stumpf, C. R.; Lu, J.; Thomas, J. D.; Madore, S. J. Nucleic Acids Res. 2000, 28, 4552. (16) Vainrub, A.; Pettitt, B. M. Phys. Rev. E 2002, 66, 041905. (17) Vainrub, A.; Pettitt, B. M. Biopolymers 2003, 68, 265. (18) Chou, C. C.; Chen, C. H.; Lee, T. T.; Peck, K. Nucleic Acids Res. 2004, 32, 99 (E). (19) Ramdas, L.; Cogdell, D. E.; Jia, J. Y.; Taylor, E. E.; Dunmire, V. R.; Hu, L.; Hamilton, S. R.; Zhang, W. BMC Genomics 2004, 5, 35. (20) Vainrub, A.; Pettitt, M. B. J. Am. Chem. Soc. 2003, 125, 7798. (21) Patole, S. N.; Pike, A. R.; Connolly, B. A.; Horrocks, B. R.; Houlton, A. Langmuir 2003, 19, 5457–5463. (22) Pack, S. P.; Kamisetty, N. K.; Nonogawa, M.; Devarayapalli, K. C.; Ohtani, K.; Yamada, K.; Yoshida, Y.; Kodaki, T.; Makino, K. Nucleic Acids Res. 2007, 35, e110–e110. (23) Wong, K.-Y.; Pettitt, M. B. Theor. Chem. Acc. 2001, 106, 233. (24) Wong, K.-Y.; Pettitt, M. B. Biopolymers 2004, 73, 570. (25) Jayaraman, A.; Hall, C. K.; Genzer, J. Biophys. J. 2006, 91, 2227. (26) Jayaraman, A.; Hall, C. K.; Genzer, J. J. Chem. Phys. 2007, 127, 144912. (27) Wong, K.-Y.; Vainrub, A.; Powdrill, T.; Hogan, M.; Pettitt, M. B. Mol. Simul. 2004, 30, 121. (28) Law, M.; Kind, H.; Kim, F.; Messer, B.; Yang, P. Angew. Chem., Int. Ed. 2002, 41, 2405. (29) Li, C.; Zhang, D. H.; Liu, X. L.; Han, S.; Tang, T.; Han, J.; Zhou, C. W. Appl. Phys. Lett. 2003, 82, 1613. (30) Popovich, N. D.; Wong, S. S.; Ufer, S.; Sakharani, V.; Paine, D. J. Electrochem. Soc. 2003, 150, 255. (31) Zeng, J.; Krull, U. J. Chem. Today 2003, 21, 48. (32) Tangaraju, B. Thin Solid Films 2002, 402, 71. (33) Rajh, T.; Zaponjic, Z.; Liu, J.; Dimitrijevic, N. M.; Scherer, N. F.; Vega-Arroyo, M.; Zapol, P.; Curtiss, L. A.; Thurnauer, M. C. Nano Lett. 2004, 4, 1017. (34) Zapol, P.; Curtiss, L. A. J. Comput. Theory Nanosci. 2007, 4, 222. (35) Rosei, F.; Schunack, M.; Naitoh, Y.; Jiang, P.; Gourdon, A.; Laegsgaard, E.; Stensgaard, I.; Joachim, C.; Besenbacher, F. Prog. Surf. Sci. 2003, 71, 95. (36) Wang, Y.; Yamachika, R.; Wachowiak, A.; Grobis, M.; Crommie, M. F. Nat. Mater. 2008, 7, 194. (37) Zhang, H. L.; Chen, W.; Huang, H.; Chen, L.; Wee, A. T. S. J. Am. Chem. Soc. 2008, 130, 2720. (38) Langner, A.; Tai, S. L.; Lin, N.; Chandrasekar, R.; Ruben, M.; Kern, K. Angew. Chem., Int. Ed. 2008, 47, 16996. 24245
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