DNAzyme-Based Logic Gate-Mediated DNA Self ... - ACS Publications

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DNAzyme-based Logic Gate-mediated DNA Self-assembly Cheng Zhang, Jing Yang, Shuoxing Jiang, Yan Liu, and Hao Yan Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.5b04608 • Publication Date (Web): 09 Dec 2015 Downloaded from http://pubs.acs.org on December 9, 2015

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DNAzyme-based Logic Gate-mediated DNA Self-assembly Cheng Zhang1,3, Jing Yang2,3‡, Shuoxing Jiang3, Yan Liu3*, Hao Yan3* 1

Institute of Software, School of Electronics Engineering and Computer Science, Peking University, Beijing, China 2 School of Control and Computer Engineering, North China Electric Power University, Beijing, China 3 School of Molecular Sciences, Center for Molecule Design and Biomimetics at the Biodesign Institute, Arizona State University, Tempe, Arizona

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ABSTRACT: Controlling DNA self-assembly processes using rationally designed logic gates is a major goal of DNA-based nanotechnology and programming. Such controls could facilitate the hierarchical engineering of complex nanopatterns responding to various molecular triggers or inputs. Here we demonstrate the use of a series of DNAzyme-based logic gates to control DNA tile self-assembly onto a prescribed DNA origami frame. Logic systems such as “YES,” “OR,” “AND,” and “logic switch” are implemented based on DNAzyme-mediated tile recognition with the DNA origami frame. DNAzyme is designed to play two roles: (1) as an intermediate messenger to motivate downstream reactions and (2) as a final trigger to report fluorescent signals, enabling information relay between the DNA origami-framed tile assembly and fluorescent signaling. The results of this study demonstrate the plausibility of DNAzyme-mediated hierarchical self-assembly and provide new tools for generating dynamic and responsive self-assembly systems.

KEYWORDS: DNA self-assembly, DNA origami, DNAzyme, logic gates


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DNA-based self-assembly via sequence-specific hybridizations connecting branched junction motifs can form a large variety of DNA tile building blocks and higher-order structures, 1-6 as well as more complex patterns such as DNA origami nanostructures.7-11 As an informationcoding polymer, DNA is an obvious candidate for use in a dynamic and hierarchical selfassembly system capable of information processing. Indeed, DNA has been exploited for molecular information processing via various functional properties such as DNAzyme-catalyzed reactions,12-14 aptamer-target binding,15,16 and toehold-based strand displacement.17-19 DNAzymes are particularly appealing because they are easily synthesized and allow for catalytic signal amplification and cascading.20,21 In this study, we report a logic system for nanopatterning that uses double-crossover (DX) tiles to fill frames in a preformed DNA origami structure following programmed triggers. Different logic operations can be implemented to generate different patterns. By introducing DNAzyme at the filling site, the structural change information can be transformed into a fluorescent signal to reveal pattern growth. Initially, the simple logic gate operations of “YES” and “OR” are performed to demonstrate reliable system operation based on direct filling of DX tiles into the DNA origami frame (reported as increased fluorescent signal). A two-layer logic switch was also developed in which tile filling is triggered by DNAzymecatalyzed DNA strand cleavage. We further established a two-layer cascading “AND” gate where the two DNA tiles filling processes are organized sequentially. It should be noted that DNAzyme serves both as an output to report the status of the reaction by fluorescence and as an input or intermediate for triggering downstream reactions. The logic gates for DNAzymemediated DNA nanopatterning integrate the advantages of diverse structural patterning and enzymatic signal cascading.


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Figure 1. Schematic illustration of a “YES” gate using DNA tile A as the input. (a) DNA origami K1 is generated by folding a single strand of M13mp18 DNA with designed staple strands. It contains two holes (H1 and H2) that serve as filling frames. Single-stranded DNA overhangs (5 nt extended from the staple strands) located at the inner edges of the holes act as sticky ends to allow the DX tiles with matching lengths and sticky ends to fit inside the holes. Every other sticky end is extended with a sequence containing one-half of a single-stranded DNAzyme-1 (yellow, 7-nt arm region and a 6+6-nt recognition region). (b) DNA DX tile A (red, four helical turns long) can fit into hole H1 by attaching to the inner sides of the DNA origami frame via four unique 5-nt-long sticky ends. Two of the four sticky ends of tile A (on opposite ends) are extended with the other half of the single-stranded DNAzyme-1 (yellow), so that upon sticky end association and DX tile A filling into H1, the two halves of the DNAzyme-1 join and become catalytically active upon substrate binding. The substrate ArB (15 nt) is functionalized with fluorophore FAM (red dot) and quencher BHQ (black dot) and contains a ribonucleotide (DNAzyme-1 cutting site) in the middle. ArB can hybridize to the newly formed complete DNAzyme-1 (recognition region) and is then cleaved at the ribonucleotide. The resulting shorter strands have decreased binding affinity to the DNAzyme, and release of the FAM-labeled fragment reports the generation of the catalytically active DNAzyme (i.e., completion of tile filling in the origami frame) via an increase in fluorescence signal. (c) and (d) Atomic force microscopy (AFM) images of the DNA origami frame alone and in the presence of tile A, respectively. The unassembled loop of M13mp18 ssDNA (dotted circle) at one corner close to H2 is visible under AFM and is used as an asymmetric marker to indicate the origami’s orientation. Scale bars in the AFM images indicate 100 nm. (e) Time-dependent fluorescent signals reporting the “YES” gate result.


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The basic principle for the “YES” logic gate based on DNA origami patterning is shown in Figure 1a-b. The design consists of two structural components: DX tile A and origami K1. The origami K1 (128.5 × 72 nm) contains two holes (H1 and H2), both of which have unique extended sticky ends on the inner edges of the DNA duplexes with a transverse distance of 14.3 nm, equal to the length of DX tile A (4 full DNA helical turns in length, Figure S1). The inner cavity of each hole can accommodate up to 8 DX tiles arranged in parallel fashion. Accordingly, each DX tile A displays four sticky ends that can cooperatively bind to the corresponding sticky ends on the inner edges of H1 but not those of H2 (Figure S2). When the DNA origami and DX tile A are mixed together in a 1:16 molar ratio (DX tile A in excess), tile A is expected to completely fill up H1. The filling reaction was carried out in a mixture of 1× TAE/Mg2+ and 1× HEPES buffers by incubation at 25°C for 8-16 hours (see Supporting Information for details). Tile A was purified by cutting the band from the agarose gel to remove any incomplete products, and DNA origami K1 was purified with 100-kD MWCO filter column centrifugation to remove excess staple strands. In the presence of tile A, DX tile A spontaneously fills the DNA origami frame. As shown in AFM images (Figure 1d), only H2 can be observed after adding tile A; H1 disappears as it is completely filled. To monitor the reaction in real time, Mg2+-dependent E6-type DNAzymes at the tile-binding sites are introduced that enable transduction of the structural change information into a fluorescent signal change. DNAzyme-1 is divided into two subunits tethered at two of tile A’s sticky ends and the corresponding sticky ends at the inner sides of hole H1. Two complete functional DNAzyme-1 subunits form at the interface of tile A and hole H1 when tile A fills into the hole upon sticky end association (Figure 1b). The DNAzyme-1 substrate ArB (15 nt,


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containing a ribonucleotide unit in the middle) is functionalized with a pair of fluorophorequenchers (FAM-BHQ) on the two ends. The complete DNAzyme-1 recognizes if DX tile filling occurs in the presence of ArB (1:45 molar ratio of origami:ArB). ArB cleavage at the specific internal ribonucleotide site (TrAGG) separates the fluorophore (FAM-) and quencher (BHQ-) labeled half strands. The shorter strands (7 and 8 nt, respectively) lose their cooperative binding abilities and have decreased binding affinities with the DNAzyme; thus, both dissociate from the DNAzyme, which increases the fluorescent signal (Figure 1e, red curve). The fluorescent signal change therefore indicates formation of the complete functional DNAzyme-1, allowing real-time monitoring of the tile filling process. In contrast, almost no fluorescent enhancement is observed in the absence of tile A (Figure 1e, black trace). This result demonstrates that the introduction of DNAzyme enables corresponding connections between structural pattern formation and fluorescence signal output. To implement an “OR” gate, origami K1 is filled using two DX tiles of A and B as two inputs to specifically fill holes H1 and H2, respectively. Figure 2 depicts the design of the “OR” gate such that addition of either tile A or B can result in different filling patterns and the formation of the functional DNAzyme-1. The fluorescent reporter of both filling events is the same FAM-labeled strand generated by ArB cleavage. The AFM results demonstrate that adding either tile A or B leads to only one of the two holes being filled (Figure 2a&b). Here, H1 and H2 can be distinguished by the asymmetric designs of the origami frame: (1) unequal side width of the frame (the left and right sides are 30.3 and 35.7 nm wide, respectively) and (2) an origami tail consisting of the unassembled loop of the M13mp18 ssDNA that is located at the corner closer to hole H2 (Figure 1a&c and S3, dotted circle). Notably, tile B cannot completely fill H2 as well as tile A fills H1 (Figure 2b). One possible reason may be a tiny structural deformation of


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H2 caused by the adjacent assembly seam on the right side of the frame (Figure S3, rectangle). When both tiles A and B are added, both H1 and H2 can be filled simultaneously (Figure 2c, more AFM images can be found in Figure S4).

Figure 2. (a)-(c) Schematic illustrations of the “OR” gate using tiles A and/or B as inputs. The AFM images showing the different filling patterns are presented on the right. (d) Timedependent fluorescent signals of the logic operations in the presence of ArB. The black trace shows no change in fluorescent signal in the absence of tiles. Curves 2, 3, and 1 show the fluorescence signal changes in the presence of tiles A, B, and both A/B, respectively.


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Accordingly, the fluorescence results (Figure 2d) are consistent with the expectation that the signal increases when either tile A or B is added. When both tiles are present, the fluorescence signal enhancement is faster than those triggered by either tile alone. The faster kinetics can be attributed to more rapid generation of DNAzyme-1 when both tiles A and B are simultaneously filling the two holes. Interestingly, the fluorescence enhancement triggered by tile A is faster than that of tile B; this can be explained by the structural deformation of H2 mentioned above, which may hinder tile B from filling H2. In the absence of any input tiles, there is no increase in fluorescent signal because no functional DNAzyme-1 can be generated (curve 4). To achieve remote control of the filling pattern, we also designed a two-layer logic switch that can be triggered by DNAzyme-2 (Figure 3a). First, tile A is pre-protected using ssDNA P1 and P2, which hybridize with the toeholds extended from the sticky ends on the two ends of tile A to form the tile LA (locked tile A). The specific sequence of TrACC (rA: ribonucleotide A) is included in the middle of both P1 and P2, providing a cleavage site for DNAzyme-2 (Figure S2&6). Such protection sterically inhibits sticky end interactions, thus preventing tile LA from filling H1 of origami K1. Upon treatment with DNAzyme-2, both P1 and P2 on tile LA can be cut into two short pieces, inducing instability and dehybridization between the protectors and tile A. The length of the hybridization region between P1 and P2 with the toehold region of the sticky ends is optimized at 11 bp (Figure S5). By optimizing the lengths of hybridizing regions between tile A and the protectors, binding stability can be precisely controlled so that the protector strands reliably associate with tile A before cleavage. After cleavage, the half protectors effectively dissociate from tile A at room temperature, unlocking tile A (Figure S5). With its sticky ends more exposed, unlocked tile A can fill into H1 and activate DNAzyme-1


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when its two halves come together; this results in an increased fluorescence signal in the presence of ArB. The specific structure of DNAzyme-2 is shown in Figure S6. Figure 3b depicts the native polyacrylamide gel electrophoresis (PAGE) results showing the protection and reactivation of tile A. The tile LA band (Lane 4) migrates slightly slower than that of tile A (Lane 1), which is consistent with its higher molecular weight and the complex looped structures on both ends of the tile. In the presence of DNAzyme-2, the band in Lane 5 runs faster than that of tile LA in Lane 4, suggesting DNAzyme-mediated protector strand cleavage and dissociation of the cleaved protectors from tile A. The AFM images (Figure 3c&d) provide direct visualization of the DNAzyme-triggered logic switch. In the absence of DNAzyme-2, although the origami K1 and tile LA are co-incubated for 3-6 hours, both holes in almost all of the origami remain empty. In the presence of DNAzyme-2, AFM shows that only one hollow hole remains, implying that the tile LA is effectively unlocked, allowing it to fill one of the holes (more AFM images can be found in Figure S7). Furthermore, the “YES” answer of the logic switch leads to DNAzyme-1 activation, which facilitates scission of F-Q-labeled ArB and a subsequent increase in fluorescence signal (Figure 3e). Upon adding tile LA in the presence of DNAzyme-2 (curve 2), the rate of fluorescence increase is much higher than that without the DNAzyme (curve 3). Notably, although tile LA is designed to inhibit filling without unlocking, some degree of fluorescent leakage can be observed (curve 3). This indicates that the protection of tile A by P1 and P2 is not 100% effective; some tile LA may still fill into the origami hole without being precleaved by DNAzyme-2. This is consistent with the AFM results (Figure 3c) showing that the inner edges of the hole appear less clear-cut with a small degree of filling. In the fluorescence experiment, when tile A (unprotected) is added (curve c), a higher rate of fluorescence increase is observed due to a lack of inhibition of the sticky end interactions. When the concentration of


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Figure 3. Schematic illustrations of the two-layer logic switch. (a) The two ends of tile A are protected by pre-hybridization with protectors P1 and P2 and thus could not directly fill into the origami. P1 and P2 are both 38-nt-long, single stranded, and contain a 15-nt central loop with a ribonucleotide in the middle, making them DNAzyme-2 substrates. The two portions near the


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ends of P1 and P2 hybridize to the toeholds extended from the two sticky ends on both ends of tile A (optimized to 11 bp, see details in Figure S5). In the presence of DNAzyme-2, P1 and P2 are each cleaved into two shorter pieces, thereby losing their binding cooperativity with tile A and unlocking tile A. (b) PAGE results showing locking and unlocking of DNA tile A. Lane 1, tile A alone; lane 2, tile A with P1; lane 3, tile A with P2; lane 4, locked tile A with both P1 and P2 (tile LA); lane 5, tile LA in the presence of DNAzyme-2. The 8% native polyacrylamide gel was run in 1× TAE-Mg2+ buffer and stained with ethidium bromide. (c) and (d) AFM images of origami K1 and tile LA (1:16 molar ratio of origami:tile) in the absence and presence of DNAzyme-2, respectively. (e) Time-dependent fluorescence signals in the presence of ArB. Curve 3 presents tile filling using with LA. Curves 2 and 3 use tile LA with and without DNAzyme-2 trigger, respectively, and curve 1 use tile A directly without any protection or trigger. Here, tile A contains the extended toeholds for potential binding with P1 and P2 and without being protected.

DNAzyme-2 was varied from 2-240 nM in the presence of tile LA (Figure S8), the rate of fluorescence change and the reported fluorescent intensity increase accordingly. More DNAzyme-2 increases the availability of activated tile A, which enhances the rate of tile A filling into the origami hole. We further extend the computation to perform a cascading “AND” gate to control DNA origami-framed patterning using a sequential “tile-after-tile” filling strategy (Figure 4a). In this sequential filling system, the origami patterning process is divided into two steps: (1) filling of tile A into H1, which enables (2) filling of tile C into H2. Tile LC is locked tile C that is prehybridized to protectors P3 and P4, which both contain the ArB sequence that is a DNAzyme-1 substrate (Figure S2). In the presence of tile A only, H1 of origami K2 can be filled directly. Meanwhile, DNAzyme-1 (yellow) is generated at the interface of H1 and tile A. In the absence of tile LC, the reaction stops here with no increase in fluorescent signal because CrD, the substrate of DNAzyme-3, is chosen as the final fluorescent reporter. On the other hand, when only tile LC is present, both holes cannot be filled because the protected sticky ends of tile C prevent effective interactions between the sticky ends. Since no active DNAzyme-3 (purple) can


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be generated, no fluorescence signal change is expected. With the co-input of both tiles A and LC, the DNAzyme-1 generated by tile A filling triggers the unlocking of tile LC by cleaving the protectors on both sides of tile LC, allowing it to fill H2. At the same time, complete and catalytically active DNAzyme-3 (purple) is generated at the interface between H2 and tile C and cleaves the F-Q-labeled CrD, increasing the fluorescence output.

Figure 4. (a) Design of a cascading “AND” gate. Logic operation activation is based on filling both of holes in origami K2 with two different DNA tile inputs: tile A and locked tile C (tile LC). DNAzyme-1 (yellow) and DNAzyme-3 (purple) are required to implement the logic gate, but only DNAzyme-3 targeting of reporter CrD can result in increased fluorescent signals. AFM results are shown for three conditions: in the presence of (b) tile A only, (c) tile LC only, and (d)


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both tiles A and LC. The scale bars are 200 nm. (e) Time-dependent fluorescent signals. Curves 1, 2, and 3 represent the changes triggered by tile A, tile LC, and both tiles, respectively. The AFM results of the operating “AND” gate are depicted in Figure 4b-d. With tile A only, one hole is filled while the second remains empty. With only tile LC, both holes remain open, which indicates that the protection on the sticky ends effectively inhibits tile LC from filling into the origami frame. When both tiles A and LC are introduced together, both holes are filled with tiles, allowing successful implementation of the cascading “AND” gate control of the patterning process in which upstream tile filling triggers and controls downstream filling pattern (additional AFM images can be found in Figure S9). Meanwhile, the time-dependent fluorescent signals depict the results. No change in curve 1 is observed in the presence of tile A, whereas a significant signal increase in curve 3 is obtained in the presence of both tiles A and LC; these outputs reflect the expected results “no” and “yes,” respectively. A “no” result is expected when only tile LC is introduced; however, the fluorescent intensity shows a slight increase (curve 2). This can be attributed to incomplete locking of tile LC and slow filling into the origami frame. In summary, we have developed a programmable molecular logic operation system that generates a pattern on a DNA origami frame in a controllable manner, based on DNAzymemediated assembly. The logic operation design enables information to be processed between the DNA origami structural pattern generation and enzymatic signal transduction. Furthermore, the modular design of origami may allow the implementation of more complex signaling circuits because patterns can be controlled in a cascading way. The major deficiency of this DNAzymemediated system is unspecific filling leakages between the tiles and origami. Thus, more efficient methods for protecting and releasing DNA tile should be developed in future work, possibly by introducing proteins or structural switching aptamers to control origami modularization. The successful implementation of the logic operations shown here proves that


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DNAzyme-mediated DNA self-assembly can be used to construct cascading logic gates and achieve controllable information delivery. AUTHOR INFORMATION Corresponding Author *Email: [email protected] *Email: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. ACKNOWLEDGMENT The authors acknowledge financial support from the Army Research Office MURI award W911NF-12-1-0420 and National Science Foundation award 1334109 to H.Y. & awards from National Natural Science Foundation of China (61272161, 61370099, 61425002, 61320106005, and 61571189) to C. Z and J. Y.

ABBREVIATIONS AFM, atomic force microscopy; DX, double-crossover; PAGE, polyacrylamide gel electrophoresis; ssDNA, single-stranded DNA. REFERENCES (1) Winfree, E.; Liu, F. R.; Wenzler, L. A.; Seeman, N. C. Nature 1998, 394, 539-544.


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