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Aptamer-Binding Directed DNA Origami Pattern for Logic Gates Jing Yang,†,‡ Shuoxing Jiang,‡ Xiangrong Liu,§ Linqiang Pan,*,∥ and Cheng Zhang*,‡,⊥ †

School of Control and Computer Engineering, North China Electric Power University, Beijing 102206, China Department of Chemistry and Biochemistry Center for Molecule Design and Biominetics at the Biodesign Institute, Arizona State University, Tempe, Arizona 85287, United States § Department of Computer Science, Xiamen University, Xiamen 361005, China ∥ Key Laboratory of Image Information Processing and Intelligent Control, School of Automation, Huazhong University of Science and Technology, Wuhan 430074, China ⊥ Institute of Software, School of Electronics Engineering and Computer Science, Peking University, Beijing 100871, China ‡

S Supporting Information *

ABSTRACT: In this study, an aptamer-substrate strategy is introduced to control programmable DNA origami pattern. Combined with DNA aptamer-substrate binding and DNAzyme-cutting, small DNA tiles were specifically controlled to fill into the predesigned DNA origami frame. Here, a set of DNA logic gates (OR, YES, and AND) are performed in response to the stimuli of adenosine triphosphate (ATP) and cocaine. The experimental results are confirmed by AFM imaging and timedependent fluorescence changes, demonstrating that the geometric patterns are regulated in a controllable and programmable manner. Our approach provides a new platform for engineering programmable origami nanopatterns and constructing complex DNA nanodevices. KEYWORDS: DNA origami, aptamer, DNAzyme, tile filling, logic gate

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properties and stability in chemical reacitons.39−41 Recently, DNA aptamer was implemented to establish numerous nanodevices and sensors.39−43 It is, however, still of great interest to develop more programmable ways to regulate origami frame patterns, via the property of aptamer-substrate binding. Herein, we developed a pattern-based DNA origami logic system in response to two low-molecular-weight stimuli, adenosine triphosphate (ATP) and cocaine. Combined with DNA aptamers and DNAzyme, these small molecules are used as “input” signals to guide the small DNA tiles to fill into the specific cavities predesigned in the origami to generate different patterns and fluorescence signal outputs. Triggered by the stimuli, a series of “logic gates” (OR, YES, and AND) are achieved. On the other hand, we also focus on the “lock/ unlock” strategies to control the patterning process by aptamertarget binding and DNAzyme-cutting, respectively. AFM and a

INTRODUCTION DNA molecules are powerful materials for the programmable construction of nanostructures in a precisely defined manner.1−3 Recently, the technique of DNA origami is developed to generate well-defined geometric nanostructures involving two-dimensional (2D) patterns,4−8 nanotubes,9−14 and 3D wireframe polyhedra.15−20 Thus, the versatility and predictability of DNA origami make it an excellent platform for engineering nanopatterns in a predesigned and programmable manner. Actually, the origami-based nanopatterns have been applied in many fields ranging from nanodevices21−26 to biosensors.27−29 In particular, to establish visualized molecular systems, many origami based systems are designed by changing pattern-configurations when responding to specific stimuli, including metal ion,30−32 and protein,33−36 and nucleic acids.37,38 In this way, the external molecular triggering signals can be translated into structural information on pattern reconfigurations. Besides, aptamer is also an ideal engineering trigger, with binding abilities to specific low-molecular-weight molecules. For example, ATP and cocaine are commonly used to recognize aptamer sequences for their specific binding © 2016 American Chemical Society

Received: August 18, 2016 Accepted: November 21, 2016 Published: November 21, 2016 34054

DOI: 10.1021/acsami.6b10266 ACS Appl. Mater. Interfaces 2016, 8, 34054−34060

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ACS Applied Materials & Interfaces fluorescence reader were used to study the outputs of our DNA origami system.

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EXPERIMENTAL SECTION

Assembly of DNA Origami Frame. The helper strands were divided into three groups such as G1 (192 strands), G2 (16 strands), G3 (16 strands), and G4 (16 strands) (DNA sequences in Supporting Information). The origami frame-1 was assembled by mixing M13mp18 DNA (10 nM) with the helper strands G1, G2, G3, C-A, E-A, C-B, and E-B in a 1:10 molar ratio in 1 × TAE/Mg2+ buffer (pH 8.0, 20 mM Tris base, 20 mM acetic acid, 2 mM EDTA, 12.5 mM Mg(OAc)2). Similarly, the origami frame-2 was assembled by mixing M13mp18 DNA with the helper strands G1, G2, G4, C-A, E-A, C-C, E-C, and the frame-3 was formed by adding the helper strands G1, G2, G3, C-A, E-A, C-D, and E-D. The final volume of the reaction was 100 μL. The origami solution was annealed for two steps: (1) the temperature decreased from 90 to 70 °C at a rate of 1 °C every 1 min, from 70 to 30 °C at a rate of 1 °C every 15 min, then from 30 to 25 °C at a rate of 1 °C every 10 min, and finally kept at 4 °C and (2) the helper strands C and E in the same equimolar ratio were added into the origami solution 1, 2, 3, respectively, at a temperature of 45 °C and then cool down (at a rate of 1 °C every 5 min). Finally, to remove the excess helper strands, the origami frames were washed with 1 × TAE/ Mg2+ buffer eight times using a 100 kDa MWCO Microcon centrifugal filter device. Assembly of DNA DX Tiles. Each DX tile was assembled by mixing all the strands in the tile in an equimolar ratio (3 mM) in 100 μL 1 × TAE/Mg2+ buffer. The solution was annealed in a PCR thermocycler with the temperature decreased from 90 to 24 °C at a rate of 2 °C every 5 min, and then kept at 24 °C. After annealing, the DX tiles were purified using 8% native polyacrylamide gel electrophoresis in 1 × TAE/Mg2+ buffer. The purified tiles A and C were then reconstituted in 1 × TAE/Mg2+ buffer, and the tiles B and D were dissolved in 1 × Tris/NaCl buffer (25 mM TrisHCl and 400 mM NaCl). The concentrations of DX tiles were measured by absorbance at 260 nm. Finally, the sticky ends of tile A was protected by strands PA1 and PA2 in an excess molar ratio at 25 °C for 8 h. Similarly, the sticky ends of tiles B, C, and D were also protected by strands PB1 and PB2, PC1, and PC2, PD1, and PD2, respectively. Fluorescent Biosensing Assays. In ATP assays of “OR” gate, 8.8 nM of the origami frame-1 solution was incubated with a series of ATP concentrations (0, 1 μM, 10 μM, 100 μM, 1 mM) in 1× TAE/Mg2+ buffer and 1× Hepes buffer, and fluorescence intensities were recorded every 2 min. In ATP assays of “YES” gate, a series of ATP concentrations (0, 10 μM, 100 μM, 1 mM) were performed in the same conditions. In cocaine assays of “AND” gate, 8.8 nM of the origami frame-3 solution was incubated with a series of cocaine concentrations (0, 200 μM, 400 μM, 600 μM) in 1 × TAE/Mg2+ buffer and 1× HEPES buffer, and fluorescence intensities were recorded every 2 min. All fluorescence experiments were repeated three times to ensure reproducibility. The fluorescent experiments were implemented using real time PCR (Agilent, Mx3005P). AFM Images. The AFM images were obtained using a Dimension FastScan AFM (Bruker). First, 3 μL of sample (1.6 nM) was deposited onto a prepared cleaved piece of mica (Ted Pella, Inc.) and left for 2 min. Then 100 μL of 1× TAE/Mg buffer was added on the top of the sample. Finally, the sample was imaged in ScanAsyst in Fluid mode, using ScanAssyst Fluid+ probes (Bruker).

Figure 1. Principle of the patterns of DNA tile filling into origami frame. (a) Scheme of tile A filling into the hole H1 of the origami frame. Two hollow holes with dimensions 14.3 nm × 48 nm contain eight single-stranded overhangs per side (5 nt extended from the helper strands). The DNA overhangs located at the inner edges of the holes act as sticky ends to allow DX tiles of matching length and sticky ends to fit inside the holes. The yellow curved strands at the ends of the tiles and the inner edge of the origami consist of DNAzyme and the sticky ends of tile A. The distance from the H1 to the left edge (30.4 nm) is narrower than the distance from the H2 to the right edge (35.7 nm). In the presence of tile A, H1 is fully filled due to the specific recognition of sticky ends. (b) The specific origami frame and DX tiles were designed by Tiamat software. (c) AFM images before and after filling. Scale bars indicate 100 and 200 nm.

mentary to the overhangs of the holes. In the presence of tile A, the guided pattern of the DNA tiles filling into the origami frame occurs spontaneously owing to the hybridization between the specific sticky ends (the ratio of the origami frame to tile A was chosen as 1:16 (Figure S3)). After filling, only one hollow hole H2 can be observed via AFM imaging (Figure 1c). To conveniently distinguish the two holes, we used an asymmetric origami frame design with unequal side widths (left: 30.3 nm; right: 35.7 nm). Additionally, the origami frame also contains a tail at the corner closer to H2 comprising the unassembled loop of the M13mp18 ssDNA (Figure 1a). By controlling the tilefilling process to generate different origami patterns (only H1 or H2 filled or both filled), we performed a series of logic gates (OR, YES, and AND) to demonstrate the feasibility and operability of the design. First, an “OR” logic gate was established based on the “lock/ unlock” strategy of aptamer-binding (Figure 2a). In the locking step, both tile A or B can be deactivated by hybridizing with the protector strands PA or PB (details in Figures S1 and S2), which contain aptamer-recognizing sequences of ATP and cocaine in the middle region, respectively. They bind at the end of the tiles A and B to form the protected tile L-A or L-B, respectively, which loose the capability to fill in the cavities in the origami due to the closure of their sticky ends. Then, in the “unlocking” step, the protector strands (PA or PB) at the ends of the L-A or L-B can be removed by adding the aptamer target

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RESULTS AND DISCUSSION As illustrated in Figure 1, we designed a rectangular DNA origami frame (128.5 nm × 72 nm × 2 nm) with two holes (H1 and H2), comprising a ∼7000 nt circular single-stranded M13mp18 DNA and 240 short staple strands. Each of the holes has extended sticky ends from the helper strands of the inner edges, and can accommodate eight double crossover (DX) tiles. Here, DX tile A is designed to fill into H1, with a length of four full helical turns and specific extended sticky ends comple34055


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Figure 2. Operations of the “OR” logic gate using a DNA origami pattern including origami frame-1 and protected tiles L-A and L-B. (a) Illustration of the “OR” gate using ATP and cocaine as two independent inputs to trigger the filling patterns. (b) AFM images give a direct visualization of the various filling patterns in the presence of the different triggers. Scale bars indicate 200 nm. (c) PAGE results of optimizing the length of protector strand PA1. Lane 1, 10 bp DNA ladder; lane 2, tile A; lane 3, tile A with PA1−9; lane 4, tile A with PA1−9 and ATP; lane 5, tile A with PA1−10; lane 6, tile A with PA1−10 and ATP. (d) Time-dependent fluorescence intensity changes with different inputs. Time interval is 2 min. (1) ATP and cocaine, (2) ATP alone, (3) cocaine alone, and (4) no input. All data represent the average of three replicates. Error bars represent one standard deviation from triplicate analysis.

pattern with no hole observable (Figure 2b and S6d). Notably, some incomplete filling patterns especially around H2 still remained. The low efficiency of the tile B filling might come from the frame structural deformation induced by the designed seam near the H2 (Figure 1a). To better monitor the filling results, Mg2+-dependent E6type DNAzyme-1 was introduced to transform the structural change information into fluorescence signal changes.44,45 As demonstrated in Figure 2a, DNAzyme-1 comprises two subunits, where one-half (19 nt) is extended from one of the sticky ends on each side of the DX tiles, and the other half (22 nt) is extended from the termini of the helper strands from the holes (Figure 2a). The extension of the DNAzyme-1 subunits sequences from the sticky ends does not affect the tiles-holes recognition. Upon tiles filling into the holes, the complete DNAzyme-1 is generated at the boundary of the tiles and the holes, thus becoming catalytically active. Here, a fluorescent reporter ArB (15 nt, 0.2 μM), containing a ribonucleotide cleavage site (TrAGG) in the middle region, is used to report the filling results. Fluorophore FAM and quencher BHQ are functionalized at either end of strand ArB. Thus, when complete DNAzymes are generated, the reporter ArB will be

(ATP or cocaine) that preferably bind with the aptamer sequence on the specific protector strands to form the aptamersubstrate complex (PA+ATP) or (PB+cocaine). The specific binding caused the protector strands to dissociate from the tiles to generate free tiles A or B with their sticky ends exposed. The locking and unlocking process was confirmed by native polyacrylamide gel electrophoresis (PAGE) (Figure 2c and S1). The “OR” gate system composes of the origami frame-1 and two protected tiles, L-A and L-B. Tile A and B were specifically designed to fill into holes H1 and H2, respectively. On treatment with either ATP or cocaine or both, the corresponding protected tiles could be activated and would fill into the specific holes in the origami frame to yield specific patterns (Figure 2a and b). In the presence of ATP (1 mM) (Figure S4), tile A was released from locked L-A to fill into H1, thus causing the disappearance of H1 and leaving only H2 observable (Figure 2b and S6b). Similarly, in the presence of cocaine (0.4 mM), tile L-B was activated to accommodate of tile B resulting in disappearance of H2 (Figure 2b and S6c). Furthermore, when ATP and cocaine were introduced simultaneously, tiles L-A and L-B were both activated to fill in H1 and H2, respectively, resulting in a rectangular origami 34056


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the flexible loops lack affinity for Mg2+ binding. In the first layer, addition of ATP (1 mM) allows the ATP-aptamer domain to fold into a hairpin aptamer-ATP complex, which structurally rigidifies the loop region in the DNAzyme sequence. Thus, the activated DNAzyme-2 is able to bind Mg2+ and restore its cleaving activity. Subsequently, in the second layer, the protector strands PC1 and PC2 (substrate of the DNAzyme-2) are cleaved, thus leading to the exposure of the sticky ends on tile C and allow filling of H2. After tile filling, DNAzyme-3 is generated at the boundary of the tiles and the holes (Figure 3a), which targets the fluorescent reporter CrD (15 nt, 0.2 μM) to generate a fluorescence signal increase. Similar to ArB, the strand CrD is functionalized with fluorophore (FAM) at the 5′-terminus, and quencher (BHQ) at the 3′-terminus with a ribonucleotide residue in the middle. In the presence of ATP, AFM results showed that H2 of origami frame-2 disappeared, leaving only H1 clearly visible (Figure 3b). In these AFM images, it was common to observe some incomplete filling (Figure S7b), likely from a combination of the low kinetics of the two-layer reaction process and structural deformations caused by the central seam of the origami frame close to H2. In contrast, in the absence of ATP, no active DNAzyme-2 was generated to trigger filling, and the origami had two recognizable holes (Figure 3c and S7a). In addition, we further monitored the time-dependent fluorescent intensities to test the design. When ATP was introduced, a significant fluorescent enhancement was detected (curve 1 in Figure 3d and S5), suggesting generation of active DNAzyme-2. Interestingly, the fluorescence increase was much lower than those for the “OR” gate at the same time point, indicating a slower reaction rate for the two-layer logic operations. In the control experiment, no obvious fluorescence increment could be observed in the absence of ATP (Figure 3d, curve 2). These results demonstrate the successful operation of the two-layer “YES” gate. We next established an “AND” logic gate using ATP and cocaine as the two inputs, in which a mixed operating strategy was employed including both aptamer-binding and DNAzyme activity. In the “AND” gate, the initial system composes of the origami frame-3 and the protected tile L-D form (Figure 4a). Tile D was designed to fill into H2. Notably, the extended helper strands (golden yellow) on origami frame-3 have three sections, consisting of one-half of DNAzyme-4 (Mg2+-dependent loop domains), the foreign ATP aptamer sequences, and the sticky ends (complementary to the sticky ends of tile D). Similarly, the protected tile L-D is produced by hybridization with protectors PD1 and PD2 containing cocaine aptamer sequences in the center region. First, in the presence of ATP, the protected tile L-D remained in the locked state, and could not fill into the frame despite the formation of aptamer-ATP complexes on the origami frame-3 (Figure 4a). Therefore, two hollow holes remained observable via AFM imaging (Figure 4b and S8a). In this condition, no significant fluorescent enhancement was observed (curve 1 in Figure 4c). Actually, a slight increase was still detected, possibly due to leakages from the protected tile LD filling into origami. Next, on addition of cocaine, tile L-D was activated by formation of aptamer-cocaine complexes, resulting in the tiles filling into H2, which was demonstrated by AFM results in Figures 4b and S8b. However, different from the “OR” gate, there was no corresponding increase in fluorescence (Figure 4c, curve 2). It can be explained that the incorporation of the foreign ATP aptamer sequences into the Mg2+-

recognized and cut into two pieces, leading to the FAM fluorescence increase (Figure 2a). It was observed that in the presence of either ATP or cocaine, the fluorescence signals increased significantly (Figure 2d, curves 2 and 3), consistent with the expectations. Simultaneous addition of ATP and cocaine yielded a greater increase in fluorescence signal than those for either input alone (Figure 2d, curve 1). This may arise from a larger amount of DNAzyme-1 generated from the two filling processes. However, in the absence of any input, a small amount of fluorescence was still observed, indicating some leakages still occurred in the control experiment (Figure 2d, curve 4), possibly because of imperfect locking of the tiles. To explore the versatility of the pattern strategy, a two-layer “YES” gate was constructed that included inactive DNAzyme-2, protected tile L-C, and origami frame-2 (Figure 3a). Tile C was designed to fill into H2. Here, DNAzyme-cutting is introduced as a tool to activate the tile filling via specific cleavage of the protector strands. Initially, the DNAzyme-2 is deactivated by inserting a foreign ATP aptamer sequence into the conserved loop domains, thereby inhibiting its cleaving activity because

Figure 3. Operations of the two-layer “Yes” gate using origami frame-2 and protected tile L-C. (a) Schematic of the logic gate. Inactive DNAzyme-2 (golden yellow) has an enlarged loop domain (an ATP aptamer recognizing region) in the middle of the Mg2+-dependent sequences. Active DNAzyme-2 is designed to cleave the protected tile L-C generated by hybridizing tile C with protector PC1 and PC2 to prevent direct filling into the origami. DNAzyme-3 (purple) can then cleave the reporter strand CrD to trigger fluorescent signals. (b, c) AFM images in the presence of (b) and absence (c) of ATP. Scale bars indicate 200 nm. (d) Time-dependent fluorescence intensities upon addition of ATP. The time interval is 2 min. The curve (1) presents the fluorescent result with ATP, and the curve (2) shows the result without ATP. Error bars represent one standard deviation from triplicate analysis. 34057


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Figure 4. Operations of the “AND” logic gate. (a) Scheme of the “AND” gate. The protected tile L-D is generated by hybridization with protectors PD1 and PD2. DNAzyme-4 (golden yellow) with inserted ATP aptamer sequences can cleave the reporter strand ArB when activated. (b) AFM results of three simulating ways as in the presence of ATP, cocaine, and both of them, respectively. The scale bars indicate 200 nm. (c) Timedependent fluorescent intensities at 2 min intervals. Curves 1−3 exhibit the sample triggered by ATP, cocaine, both of the two, respectively. Curve 4 presents the negative control without adding any inputs. The truth table reports the fluorescence signal. Error bars represent one standard deviation from triplicate analysis.

for the construction of complicated molecular logic circuits and nanodevices. The major deficiency of this study is, however, the unexpected fluorescence leakages owing to the unspecific tile filling. Therefore, more efficient methods of protection are still needed, for example, to optimize the lengths and sequences of the protector strands to improve the reaction specificity and locking/unlocking efficiency. The study described herein could be a versatile approach for programmable nanopattern engineering and will show potential applications for biosensing and molecular computing.

dependent loop domains greatly inhibited the DNAzyme-4 activity.1 Finally, when both ATP and cocaine were present, two conditions were satisfied: (1) formation of the aptamercocaine complex unlocked tile L-D and allowed it to fill into H2 and (2) formation of the aptamer-ATP complexes rigidified the loop sequence of DNAzyme-4 on the origami to restore its cleavage ability. In this case, AFM results demonstrate that H2 was almost fully filled with tile D (Figure 4b and S8c). At the same time, the substrate reporter ArB was cleaved by DNAzyme-4 to produce a significant increase of the fluorescent intensity (Figure 4c, curve 3).

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ASSOCIATED CONTENT

S Supporting Information *

CONCLUSION In summary, we have successfully established a series of logic operations (“OR”, “YES”, and “AND”), to programmable control the specific DX tile filling into origami cavities to generate different patterns. The strategies here were manipulated by aptamer-target binding mediated strand displacement or conformational change and bipartite DNAzyme-cutting. The computing results were confirmed by AFM imaging and timedependent fluorescence changes. In this study, the filling patterns are regulated to perform various 2D geometric configurations in a controllable and programmable manner. Moreover, via the DNAzyme-cutting strategy, the structural nanopatterning information is transformed into physicalchemical signals. Multistimuli were also adapted to achieve the basic logic gate operations, providing a promising method

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.6b10266. Experiment materials, the methods of DNA origami and DX tile assembly, fluorescent biosensing assays, AFM images, design of the DNA tiles and optimization of protected DNA strands, and additional experimental data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Cheng Zhang: 0000-0002-1131-6516 34058


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ACS Applied Materials & Interfaces Author Contributions

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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 The authors acknowledge financial support from National Natural Science Foundation of China (Grants 61370099, 6127216 1, 614 25002, 6147233 3, 6157 2046, and 61320106005). We would like to thank Prof. Hao Yan and Yan Liu for helpful discussion and careful revision.

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Aptamer-Binding Directed DNA Origami Pattern for ... - ACS Publications

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