Identification of Single Nucleotides by a Tiny Charged Solid-State

Jul 26, 2018 - Discrimination of single nucleotides by a nanopore remains a challenge because of the minor difference among the four types of single ...
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Identification of Single Nucleotides by a Tiny Charged Solid-State Nanopore Haojie Yang,†,§ Zhongwu Li,†,§ Wei Si,† Kabin Lin,† Jian Ma,† Kun Li,† Litao Sun,‡ Jingjie Sha,† and Yunfei Chen*,† †

Jiangsu Key Laboratory for Design and Manufacture of Micro-Nano Biomedical Instruments and ‡China Education Council Key Laboratory of MEMS, Southeast University, Nanjing 210096, China

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S Supporting Information *

ABSTRACT: Discrimination of single nucleotides by a nanopore remains a challenge because of the minor difference among the four types of single nucleotides. Here, the blockade currents induced by the translocation of single nucleotides through a 1.8 nm diameter silicon nitride nanopore have been measured. It is found that the single nucleotides are driven through the nanopore by an electroosmotic flow instead of electrophoretic force when a bias voltage is applied. The blockade currents for the four types of single nucleotides are unique and differentiable, following the order of the nucleotide volume. Also, the dwell time for each single nucleotide can last for several hundred microseconds with the advantage of the electroosmotic flow, which is helpful for single nucleotide identification. The dwell-time distributions are found to obey the first-passage time distribution from the 1D Fokker−Planck equation, from which the velocity and diffusion constant of each nucleotide can be deduced. Interestingly, the larger nucleotide is found to translocate faster than the smaller one inside the nanopore because the larger nucleotide has a larger surface area, which may produce larger drag force induced by the electroosmotic flow, which is validated by molecular dynamics simulations.

1. INTRODUCTION Nanopores have been considered as promising devices for single-molecule sensing with features of low-cost, inherent sensitivity, amplification-free sample preparation, and high throughput. They have provided significant insights into the research area of static and dynamic molecular activities, properties, and interactions.1−8 Reported sensing applications of nanopores include detection of proteins,9,10 nucleic acids,6,11 small molecules,12 and ions.13−15 Most noticeably of all, single nucleotide identification and DNA sequencing have already been demonstrated with biological nanopores.3,4,16,17 The Oxford Nanopore Technologies Ltd. reported that the sequence of single-stranded DNA can be read at a level of accuracy greater than 92%.18−20 Stimulated by the desire for nanopores with controllable dimensions, easier modification, and more robustness, solid-state nanopores including silicon nitride,21 silicon oxide,22 graphene,23−25 MoS2,26 and boron nitride27 have attracted a lot of intensions. During the past decade, the solid-state nanopore was able to identify only dsDNA or ssDNA translocation events.3,28,29 Recently, a lot of efforts have been made to differentiate nucleic acids by tiny solid-state nanopores. Venta et al.30 found that when poly(dA)30, poly(dT)30, and poly(dC)30 traversed small silicon nitride nanopores with the diameter ranging from 0.8 to 2 nm and length from 5 to 8 nm, the current blockage for each homopolymer transport, detected by 1 MHz bandwidth © 2018 American Chemical Society

measurement electronics, may be arranged in a decreasing order: poly(dA)30 > poly(dT)30 > poly(dC)30. Similarly, Ma et al.31 achieved the detection and discrimination of poly(dG)3 and poly(dT)3 based on differences in their physical dimensions using a 2.5 nm diameter and 8 nm thick nanopore. To realize the single base discrimination in solid-state nanopores, Feng et al.32 tried to fabricate the MoS2 nanopore. Under a viscosity gradient across the pore with roomtemperature ionic liquid and aqueous solution, they succeeded in controlling the velocities of DNA through the MoS2 nanopores. The approach can be used to statistically detect the homopolymers composed of all four types of nucleotides and even the single nucleotide by the current signatures measured during their transient residence in the narrow orifice of the atomically thin MoS2 nanopore. Wanunu et al.33 achieved the detection and discrimination of 25-bp dsDNA, 22-bp dsRNA, or phenylalanine tRNA based on differences in their physical dimensions using a 3 nm diameter and 7 nm thick membrane silicon nitride nanopore. The challenge for realizing the single nucleotide discrimination by a nanopore is that the DNA strands translocate too fast through the nanopore. To resolve this problem, nanopore-sensing systems equipped with a DNA motion controller,34 optical tweezer,35 Received: June 25, 2018 Published: July 26, 2018 7929

DOI: 10.1021/acs.jpcb.8b06056 J. Phys. Chem. B 2018, 122, 7929−7935

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The Journal of Physical Chemistry B magnetic tweezer,36 and atomic force microscope37 were tried to manipulate DNA translocation through a nanopore. All of those studies attempted to improve the spatial and temporal resolution of solid-state nanopores by using smaller diameter nanopores, thinner membranes, different solutions, more accurate detection equipment, and various DNA manipulation methods. However, all of those methods failed in identifying single nucleotides. In this paper, a Si3N4 nanopore with a charged surface was successfully fabricated to distinguish four different single nucleotides by analyzing the translocation velocity and current blockades. The key strategy of the simple Si3N4 nanopore achieving such a high resolution is that it is the electroosmotic force rather than the electrophoretic force driving single nucleotides to translocate through the pore with extremely low velocity. In order to understand the unexpected driven force on the nucleotides, we further conducted molecular dynamics (MD) simulations to analyze the underlying mechanism of the four types of single nucleotide translocation through a nanopore in detail.

(Supporting Information S1). Following the FIB milling process, a high-resolution transmission electron microscope (a FEI Titan 80-300 system operated at 300 kV) is used to drill a nanopore with diameter 1.8 nm on the thinned area. Therefore, in our experiments, a nanopore with 1.8 nm diameter (Figure 1b) and 10 nm thickness was applied. Prior to each experiment, all nanopore chips were subjected to a standard cleaning process in (3:1) H2SO4/H2O2 for 20 min and treated in an oxygen plasma environment for 5 s. The chip sealed by silicone elastomer gaskets was mounted on a polymethylmethacrylate cell, which was filled with an electrolyte solution. The electrolyte solution was 1 M KCl with 10 mM Tris-HCl and 1 mM ethylenediaminetetraacetic acid (EDTA), which was degassed, filtered, and adjusted to pH 8.0 at room temperature. All the DNA nucleotides used in this study were purchased from Takara BIO Inc. The current response for DNA translocating through the nanopore was acquired using a resistive feedback amplifier (HEKA EPC10, HEKA Elektronik) at 200 kHz with low-pass filtering at 10 kHz through two Ag/AgCl electrodes. All measurements were conducted inside a dark Faraday cage. In our experiments, the same pore was used to identify four types of a single nucleotide. After thousands of one type of nucleotide translocation events had been observed and recorded, both chambers were washed by deionized water five times and 1 M KCl with 10 mM Tris-HCl and 1 mM EDTA for another five times. After washing the chamber, we also monitored the openpore current for about 30 min to make sure no nucleotide remained in the chamber, which was validated by the observation of no nucleotide blockades. Then, another kind of nucleotide was added into the cis chamber, and the same methods were used to detect the translocation events.

2. EXPERIMENTAL DETAILS The fabrication process and experimental setup are schematically illustrated in Figure 1a. A 2.5 × 2.5 mm2 Si chip with a

3. RESULTS AND DISCUSSION In general, DNA strands are driven through a nanopore by the electrophoretic force. Considering the DNA is negatively charged in solutions, DNA strands are usually added into the chamber in which a negative electrode is inserted, which is defined as the cis side. On the trans side, a positive electrode is inserted. Once a bias voltage is applied across the nanopore, the DNA strands are driven from the negatively charged chamber to the positively charged one. At the beginning of our experiments, we added nucleotides into the cis side of the chamber with a concentration of 20 nM. However, when the chamber containing the single nucleotides was inserted with the negative electrode, none of the translocation event was detected. Instead, when we applied the bias voltage with a positive electrode in the chamber containing the sample, blocked events were observed. Figure 1c shows examples of the transient blockades that were observed when four types of single nucleotides translocated through the 1.8 nm diameter nanopore. The amplitude of the ionic current blockade, ΔI, is defined as the difference between the ionic current through the nanopore in the open state, Iopen, and that in the blocked state, Iblocked, which reads as31

Figure 1. (a) Ultrathin Si3N4 nanopore fabrication and schematic diagram of the experiment setup. (b) Bright-field TEM image illustrating a 1.8 nm diameter solid-state nanopore fabricated in a thinned Si3N4 membrane. (c) Differentiation of single DNA nucleotides in the 1.8 nm diameter Si3N4 nanopore in 1 M KCl solution. The plots stand for the ionic current trace in 6 s for each nucleotide dGTP (blue), dATP (black), dTTP (red), and dCTP (green).

200 × 200 μm2 window supporting a 100 nm thick Si3N4 membrane was fabricated by lithography and wet etching processes. The nanopore used in this study was fabricated on the free-standing low-stress Si3N4 membrane supported on the Si chip, which was achieved by focused ion beam (FIB) milling38,39 and electron beam drilling by transmission electron microscopy (TEM) on the silicon nitride film. For the purpose of discriminating single nucleotides, the nanopore must have dimensions comparable to the diameter of the nucleotide. To make sure the nanopore has a short length, FIB with a current of 24 pA was first used to mill a circle area with a diameter of 1 μm on the 100 nm thick Si3N4 film to reduce the film thickness

ΔI = Iopen − Iblocked

(1)

The observed blockade currents imply that the single nucleotides are not driven by the electrophoretic force but by the electroosmotic flow. More detailed information is provided in the Supporting Information. 7930

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Figure 2. Analysis of the blockade events induced by the translocation of single nucleotides through the nanopore. (a) Scatter plots of the blockade current versus dwell time inside the nanopore for dATP, dTTP, dCTP, and dGTP. (b) Histograms of blockade current for dATP, dTTP, dCTP, and dGTP translocation through the nanopore; the blockade current histograms can be fitted by the Gaussian distribution function (see the black Gaussian fitted curve). (c) Histograms of dwell time for dATP, dTTP, dCTP, and dGTP translocation through the nanopore; the dwell time histograms can be well fitted by the first-passage time distributions (see the black fitted line).

Figure 3. Comparison between the blockade current (ΔI, panel a), diffusion constant (D, panel b), and drift velocity (v, panel c) for different single nucleotides.

distribution shapes were fitted to the first-passage time distributions obtained from the 1D Fokker−Planck equation.41−44

The blockade events were analyzed to obtain the blockade amplitude as well as the dwell time for single DNA nucleotide translocation through the 1.8 nm nanopore. Figure 2a shows the scatter plot of the current blockade versus the translocation time for dATP, dTTP, dCTP, and dGTP. The distributions of ionic current blockade for translocation events caused by each nucleotide are plotted in Figure 2b. The black curves are Gaussian fits to the distributions. The fitting peaks of current blockades for dATP, dTTP, dCTP, and dGTP are about 146, 144, 110, and 179 pA, respectively. The blockade current strongly follows the order of the volume of each nucleotide, which could be listed in a decreasing order as G (359 Å3), A (349 Å3), T (339 Å3), and C (324 Å3).2 The structure of dNTPs used in this experiment is deoxynucleotide with triphosphate. These observations are consistent with the results obtained for single nucleotide discrimination using protein pores.3,6,16 From the fitted current blockades, dGTP and dCTP can be distinguished clearly from dTTP and dATP. However, it is still hard to discriminate dTTP from dATP. We further analyzed the dwell-time distribution by the 1D Fokker−Planck equation. The dwell-time distributions are asymmetric in shape and are characterized by sharply increasing peaks at shorter time followed by broader decays at longer time.40 The

∂ 2P(x , t ) ∂P(x , t ) ∂P(x , t ) −v =D ∂x ∂t ∂x 2

(2)

where D and v are the diffusion constant and the drift velocity of the segment for the DNA molecule inside the pore, respectively. In this model, the probability density function (PDF) P(x,t) (per unit length) of finding the pore on the position x on the DNA molecules can be obtained by solving the Fokker−Planck equation with proper boundary conditions. The first-passage PDF is defined as F1(t ) = −

d dt

L

∫−∞ P(x , t ) dx

(3)

The equation has the physical meaning of being the probability per unit time for the random walker to pass the absorbing edge assuming the DNA has fully translocated through the pore. In the equation L = l + h, l is the length of the DNA and h is the pore thickness. The result for F1(t) can be shown as 7931

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Figure 4. MD simulation results. (a) Ion and water concentration distribution along the radial direction in a 1.8 nm diameter Si3N4 nanopore connected to two chambers filled with 1.0 M KCl solution. The nanopore inner surface is assumed with the surface charge density at 0 mC/m2. (b) Average ionic current for different nucleotides inside the nanopore when a transmembrane bias was applied. (c) Water and ion velocity profile along the radial direction of the 1.8 nm diameter nanopore. The surface charge density of the nanopore was 0 mC/m2. (d) Center of mass (COM) of the nucleotides versus the simulation time. The nanopore center along the axial direction was set at 0 Å.

F1(t ) =

L 4πDt

2

3

e−(L − vt )

the four single nucleotides have the same net charge, the electrophoretic force acting on the four nucleotides from the same electric field should be equal. However, the driven force is induced by the electroosmotic flow, which is proportional to the nucleotide volume. Thus, larger volume of the single nucleotide may induce larger drag force and cause faster drift velocity. This phenomenon is clearly opposite to that by which the DNA strands are driven by the electrophoretic force, in which the larger nucleotides have the smaller drift velocity. Considering the complex interactions among the cations, anions, water molecules, and single nucleotides inside a crowded nanopore, we employed all-atom MD simulations to explore the underlying mechanisms for the drift velocity found in our experiments. The MD simulation details are described in the Supporting Information.46−48 In the MD model, the key parameter that affects the electroosmotic flow is the surface charge density. In our experiments, we used the stream potential measurement method to estimate the surface charge density of the nanopore inner surface. It is estimated that the surface charge density of the nanopore inner surface is about −8.1 mC/m2 (Supporting Information S4). In fact, we can also calculate the surface charge density of the nanopore inner surface from the I−V curves. The calculated surface charge density is about −12 mC/m2 (Supporting Information S2). In order to confirm our experimental results, we set the surface charge density in the range 0 to −53 mC/m2. First, assuming that the pore surface was not charged, Figure 4a shows the ion and water concentration profiles in a 1.8 nm diameter pore. It is clearly shown that the concentration distributions of Cl− and K+ along the nanopore radial direction are exactly similar inside the nanopore without surface charges.

/4Dt

(4)

The distributions of dwell time for dATP, dTTP, dCTP, and dGTP transport events are plotted as shown in Figure 2c. We analyzed the distributions by plotting the histograms of dwell time in Figure 2c, which can be fitted by the 1D drift-diffusion model described by eq 4. The extracted blockade current ΔI, drift velocity v, and diffusion constant D of each nucleotide obtained from the fits are shown in Figure 3. It was found that the larger single nucleotide blocked more ionic current. The blockade current for each nucleotide can be listed, in a decreasing order, as dGTP (179 pA) > dATP (146 pA) > dTTP (144 pA) > dCTP (110 pA). Figure 3b shows the diffusion coefficient, D, of each nucleotide fitted by the 1D drift-diffusion model. The diffusion coefficient for dATP, dTTP, dCTP, and dGTP are about 16.0, 25.2, 29.0, and 20.0 nm2/ms, respectively. It was found that the single nucleotide with a larger volume has a smaller diffusion coefficient, which agrees well with the prediction from the Stokes−Einstein equation.45 Figure 3c shows the drift velocity of each nucleotide through the nanopore, which can be listed in a decreasing order, as dGTP (26.39 nm/ms) > dATP (26.01 nm/ms) > dCTP (18.6 nm/ms) > dTTP (17.2 nm/ms). From the translocation velocity analysis, the dTTP and dATP can be discriminated. An interesting finding in our work is that the bigger the single nucleotide (dGTP and dATP), the faster is the drift velocity. It is postulated that the single nucleotide is driven by the electroosmotic force instead of the electrophoretic force. The electrophoretic forces act as a resistant force now because the direction of the electrophoretic force is opposite to that of the electroosmotic force. Considering that 7932

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Figure 5. MD simulation results. (a) Ion and water concentration distribution along the radial direction of a 1.8 nm diameter silicon-based nanopore with the surface charge density of −53 mC/m2 connecting two chambers filled with 1.0 M KCl solution. The black line represents the Cl− ion concentration and the red line represents the K+ ion concentration, whose values are depicted on the left vertical axis. The blue line represents the H2O concentration, whose value is shown on the right vertical axis. (b) Averaged ionic current contributed by K+ and Cl− and the total ionic current for the open pore and the pores containing nucleotides inside when a transmembrane bias was applied. (c) Water and ion velocity profiles along the radial direction inside the 1.8 nm diameter nanopore with the surface charge density of −53 mC/m2 when the nanopore connects two chambers filled with 1.0 M KCl solution. (d) COM of the four nucleotides relative to the center of the Si3N4 membrane versus the time.

increase of the surface charge density, electroosmotic flow is easily formed. It is estimated that the surface charge density in the nanopore is about −8 to −12 mC/m2. In order to save computation time, we set the surface charge density of the nanopore at −53 mC/m2 in the MD simulation. As shown in Figure 5, it is found that the Cl− ion concentration is close to zero and the K+ ion concentration is close to 2 M in the nanopore center. The reason for the Cl− ion concentration becoming dilute is that the Cl− ion suffers electrostatic repulsion from the negatively charged inner surface of the nanopore. Considering the nanopore diameter is only 1.8 nm, electric double layers almost overlap inside the whole nanopore that completely repels the co-ions. In this case, the nanopore acts as an ion sieve. Only the counter ions are allowed into the nanopore. Therefore, the K+ ion concentration inside the nanoore is higher than that in bulk solutions and the K+ ions dominate the ion transport through the nanopore. Figure 5c demonstrates that the velocity of K+ ions is much larger than that of Cl− ions, which induces a strong electroosmotic flow. The electroosmotic flow drives nucleotides through the nanopore. The initial position of DNA was set at the left end of the nanopore. Figure 5 d demonstrates that the moving direction of the nucleotides is the same as that of the K+ ions because the K+ ions drive the water and nucleotides moving together. It is found that the larger volume nucleotides G and A have larger velocity than that of nucleotides T and C, which is consistent with our experimental results.

The distribution of the ions is in good agreement with the Poisson−Boltzmann prediction within the range from the nanopore center axis to 9 Å away. Figure 4b shows the averaged ionic current with different nucleotides in the 1.8 nm Si3N4 nanopore, as the positive transmembrane bias was applied in 1 M KCl solution. The averaged baseline ionic current is 5.13 nA, whereas the averaged ionic current of each nucleotide in the nanopore, in a decreasing order, can be listed as T (4.40 nA), C (4.27 nA), A (3.62 nA), and G (3.60 nA). As we know, the blockade current of each nucleotide means the baseline ionic current minus the averaged ionic current when each nucleotide resides inside the nanopore. It is clearly shown that the blockade current of each nucleotide strongly depends on the volume of the nucleotide. Figure 4c demonstrates that the velocity of anions and cations are extremely similar when the Si3N4 surface has no surface charge, and the velocity of water is close to zero, indicating that there is no electroosmotic flow. The initial position of DNA was very close to the right side of the orifice. Figure 4d shows each nucleotide position versus the elapsed time in the nanopore and the moving direction of the nucleotide was the same as in the anions. It is easily found that the larger volume nucleotides G and A have smaller velocity than that of nucleotides T and C. In this case, the nucleotide is driven by the electrophoretic force to translocate through the nanopore. Therefore, the translocation velocity is inversely proportional to the nucleotide size. In our simulation, it is found that the electroosmotic flow strongly depends on the surface charge density. With the 7933

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causing a higher viscous drag force, whereas the electric field force caused by the net charge of all the nucleotides in the same solution should be similar. It is easy to understand that the larger nucleotides have larger velocity when the single nucleotides are driven by electroosmotic force, which is consistent with our experiment results.

Figure 6 explains both the counter ion and the co-ion velocities, while the four nucleotides reside in the nanopore.

4. CONCLUSIONS In summary, electroosmotic flow can be used to drive single nucleotides to translocate a nanopore. The blockade ionic currents can be used to statistically detect and identify the four types of nucleotides. The blockade currents follow the size order of the four types of nucleotides (dGTP > dATP > dTTP > dCTP). By analyzing the dwell time of each nucleotide translocation event, it is found that the larger single nucleotide has a smaller diffusion coefficient, in good agreement with the prediction of the Einstein relation. An interesting finding is that the larger the single nucleotide, the faster is the velocity it translocates with through the nanopore fitted from the firstpassage time distributions. MD simulations were used to unveil the mechanisms of the experimental phenomena. Our theoretical results show that cations dominate the ion transport in the nanopore, which causes electroosmotic flow to drive the single nucleotide through the nanopore. The larger volume nucleotides have higher translocation velocity because the larger volume has a larger interface with solution, which may induce a larger drag force. Our work provides a new method to control the DNA translocation speed through a nanopore, which is helpful to sequence DNA strands with solid-state nanopores.

Figure 6. (a) Force and movement analysis of the nucleotide in the neutral Si3N4 nanopore. (b) Ion and water average velocity for 1.0 M KCl solution along the axial direction in a 1.8 nm diameter siliconbased nanopore with the surface charge density of 0 mC/m2. (c) Force and movement analysis of the nucleotide in the Si3N4 nanopore with a −53 mC/m2 surface charge density. (d) Ion and water average velocity for 1.0 M KCl solution along the axial direction in a 1.8 nm diameter silicon-based nanopore with the surface charge density of −53 mC/m2.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.8b06056. Thinning the Si3N4 membrane; ion conductance measurement; electroosmotic flow; Si3N4 nanopore zeta potential calculation; and molecular dynamics simulation model (PDF)

Figure 6a,b presents the schematic diagram of the movement and force analysis of the nucleotide when the Si3N4 nanopore surface charge is neutral, and the averaged velocities of the ion and water in the nanopore under the conditions of the nanopore with or without nucleotides inside. It is clearly shown that the water velocity is close to zero inside the nanopore without surface charge, which means no electroosmotic flow is induced. In this case, the nucleotide was mainly driven by the electrophoretic force and the velocity of each nucleotide was mainly affected by the electrophoretic force and the viscous drag force. The electrophoretic force acting on each nucleotide is the same because the net charges of all the nucleotides are the same. Although a larger nucleotide has a larger interface with solution, causing a higher viscous drag force opposite to the moving direction of the nucleotide, this could be the main cause slowing down its transport velocity. Figure 6c,d presents the schematic diagram of the movement and force analysis of the nucleotide and the averaged velocities of the ions and water in the Si3N4 nanopore with surface charge density of −53 mC/m2. In this case, we can find the strong electroosmotic flow in the nanopore caused by the K+ ions dominating the ionic transport inside the nanopore. The electroosmotic flow exerts a viscous drag force on nucleotides, whose direction is opposite to that of the electrophoretic force. When the viscous drag force caused by electroosmotic flow is larger than the electrophoretic force, the nucleotide is driven by the electroosmotic flow. Under the same conditions, the larger nucleotide has a larger interface with the solution,

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhongwu Li: 0000-0001-8825-6307 Wei Si: 0000-0001-7285-058X Litao Sun: 0000-0002-2750-5004 Jingjie Sha: 0000-0002-0797-4460 Yunfei Chen: 0000-0002-8682-868X Author Contributions §

H.Y. and Z.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the financial support from the Natural Science Foundation of China (grants nos. 51435003, 51375092). Zhongwu Li is also supported by the Scientific Research Foundation of Graduate School of Southeast University (grant no. YBJJ1802). 7934

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DOI: 10.1021/acs.jpcb.8b06056 J. Phys. Chem. B 2018, 122, 7929−7935