Versatile DNA Origami Nanostructures in Simplified and Modular

Jun 27, 2017 - We introduce a simplified and modular architecture for design and construction of complex origami nanostructures. A series of basic two...
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Versatile DNA Origami Nanostructures in Simplified and Modular Designing Framework Yan Cui,†,# Ruipeng Chen,‡,§,# Mingxuan Kai,†,⊥ Yaqi Wang,† Yongli Mi,‡,§ and Bryan Wei*,† †

School of Life Sciences, Tsinghua University−Peking University Center for Life Sciences, Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China ‡ Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR § School of Chemical Science and Engineering, Tongji University, Shanghai 200092, China S Supporting Information *

ABSTRACT: We introduce a simplified and modular architecture for design and construction of complex origami nanostructures. A series of basic two-dimensional and threedimensional structures are presented. As the resulting structures can be virtually divided into blocks, modular remodeling such as translocation, contraction/extension, and bending is carried out. Structures under such a designing framework are morphable. Local conformational changes can propagate to the entire structure to reshape the global conformation. KEYWORDS: DNA nanotechnology, nanostructures, self-assembly, scaffolded DNA origami, conformational isomerization

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than that of conventional origami and can be automated easily. We constructed a series of 2-D and 3-D BLCS structures of different aspect ratios. At the same time, because a particular structure can be virtually divided into blocks, all kinds of modular remodeling can be performed to make versatile constructions derived from the same basic structure. We modified specific group(s) of connecting staples to demonstrate structural remodeling such as translocation, contraction/ extension, and bending. We also discovered that structures under such designing framework are morphable. Local conformational changes initiated by the binding of a special type of staples to the scaffold can propagate to the entire structure in a chain reaction to generate a global conformational change.22

evelopment in structural DNA nanotechnology has enabled nanostructures with extraordinary complexity.1−20 Especially, increasingly more sophisticated structures based on the scaffolded DNA origami approach have been demonstrated.9−17 Different types of origami structures have been constructed in corresponding design schemes, such as single layer with compact helices,9,13 multilayer with compact helices,10−12,14 and wireframe configuration.15−17 In a common DNA origami structure, the incredible overall complexity results from a specific routing of the “scaffold strand” and the corresponding assignment of “staple strands” to fulfill sophisticated requirements of complementarity and crossover positioning. One usually has to use dedicated software (e.g., caDNAno)21 to design and understand origami structures. Once a certain design blueprint with the sequences of a full set of staple strands is laid out, it is not always easy to make structural modifications based on it. In this study, we present a simplified architecture of DNA origami, in which scaffold routes in modular blocks are to be linked by connecting staples of standardized assignment, and we call it origami with blocks linked by connecting staples (BLCS). Two-dimensional (2-D) structures are designed in which a scaffold crosses over back and forth at each block with connecting staples linking neighboring blocks. In threedimensional (3-D) structures, individual 3-D blocks are stacked up by 2-D layers and neighboring blocks, whose stacking orientations alternate (either vertical or horizontal) and are linked together by connecting staples. Due to the standardized structural components, the designing process is less arbitrary © 2017 American Chemical Society

RESULTS AND DISCUSSION Basic Design. In origami with BLCS, the scaffold zigzags across helices to form individual blocks along the passage, with staples bridging together neighboring blocks. As a consequence, only scaffold but not staples crosses over between adjacent helices (Figure 1A, left). This is opposite to the case of conventional origami in which crossovers almost appear exclusively on staples (Figure 1A, right). The length of a typical block is 26 nucleotides (nt), and it can be translated to a rotation of ∼180° plus two times 360° Received: May 8, 2017 Accepted: June 27, 2017 Published: June 27, 2017 8199

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Figure 1. Designing framework of origami with BLCS. (A) Comparison between origami with BLCS (left) and the conventional one (right). Strands in black depict scaffolds, and strands in gray depict staples. A dashed box highlights a 2-D block in BLCS structure. Each block is abstracted as a group of parallel lines, and the entire structure is abstracted as segmented groups of parallel lines (bottom left). On the other hand, the conventional origami is abstracted as a group of continuous lines in parallel (bottom right). (B) Schematic of 2-D origami with BLCS. Top: cylinder view. Bottom left: relative rotational positions for 26 individual nucleotides of the scaffold segment along the helical path across a block (helix highlighted as a yellow cylinder and the scaffold segment highlighted in red on top panel). Bottom right: overlay of the sections shown on bottom left panel. Red arrows point at crossovers. (C) Schematic of 3-D origami with BLCS. Top: cylinder view. Bottom: layer view (staples not shown). Dashed boxes in orange highlight 2-D layers (1, 2, and 3) arranged horizontally in one block, and dashed boxes in green highlight 2-D layers (I, II, and III) arranged vertically in the neighboring block.

between any two adjacent crossovers at the opposite sides of a block (B-form DNA model is adopted with 10.5 bases per helical turn or 34.3° rotation per base), thus a planar configuration results for the full block of parallel helices (Figure 1B, bottom). Other lengths of odd multiples of halfturns, such as 16 nt, result in a similar planar configuration. As shown in Figure 1B, staples combine blocks along the x axis and crossover bundle helices along the y axis. As a consequence, all the short helices are inter-related to form a 2-D lattice. For illustrative purposes, each block is abstracted as a rectangle with a group of parallel lines and the entire structure as segmented groups of parallel lines. For 3-D rendering, scaffold zigzags in the same way as in a 2D block for one layer and continues on to another layer with

the similar routing path until the last layer to form a certain block. All the layers of one block take uniform orientation, either horizontal or vertical (Figure 1C, layers 1, 2, and 3 are horizontal, and layers I, II, and III are vertical). Two classes of orientations are arranged alternatingly, so the layers of a certain block are perpendicular to the layers of its neighboring blocks. As shown in Figure 1C, staples combine blocks along the x axis, crossovers of the horizontal layer bundle helices along the y axis, and crossovers of the vertical layer bundle helices along the z axis. As a consequence, the entire structure is bundled up along axes x, y, and z. For illustrative purposes again, each block is abstracted as a group of parallel sheets, which represent parallel layers of DNA helices. 8200

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Figure 2. Two-dimensional origami with BLCS: (A) 10B × 25H rectangle; (B) 22B × 11H rectangle. (C) Disc structure composed of 20 blocks of sector. (D,E) Patterns based on the 10B × 25H rectangle with cavities (≡ and ≡≡). (F,G) Patterns based on 10B × 25H rectangle with streptavidin decorations (X and O). Top: schematic diagrams. Bottom: atomic force microscope (AFM) images (insets show magnified views). Scale bars: 100 nm. Full-size AFM images and native agarose gel electrophoresis analysis are shown in Figures S1−S7.

Structures of Different Aspect Ratios. A standardized assignment of 26 nt blocks and the corresponding 26 nt staples (B26−S26) was tested for 2-D structures. Under such a length combination, we first designed a rectangular structure containing 10 blocks with 25 parallel helices in each block, which is referred to as the 10B × 25H rectangle (Figure 2A). Two other slimmer rectangles, 22B × 11H (Figure 2B) and 44B × 5H (Figure S4), were designed similarly. Different length combinations (e.g., B16−S32 and B16−S16) were also tested in 18B × 23H rectangles to demonstrate generality (Figure S3). Measurements show that interhelical distance is 3.0 nm for structures with 16 nt blocks, which is in good agreement with that from Rothemund flat origami. The interhelical distance was measured at 3.9−4.2 nm for the structure with 26 nt blocks, and we attribute the looser configuration to the lower crossover density along helical axes (one crossover per 26 bp). Detailed measurements can be found in Table S1 in the Supporting Information. We also designed a disc structure with 20 blocks of sectors linked by connecting staples. Each slice is designed with helices

of increasing lengths progressing away from the center (Figure 2C), and the incremental interval between neighboring helices is set to be 2 or 3 nt based on the calculation from an earlier study.13 This unorthodox design results in stark deviation from perfect compliance with helical parameters of native B-form DNA, but such a deviation does not lead to self-assembly failure or major structural deformation.10,13 Based on the 10B × 25H rectangle, several patterns with certain staples left out as cavities (Figure 2D,E) or streptavidin decoration on specific staples (Figure 2F,G) were also constructed to show that the resulting structures are fully addressable by their component staples. The same B26−S26 scheme was adopted in 3-D structures. The first example is a cuboid containing 8 blocks with 33 helices bundled as 3 helices by 11 helices (Figure 3A), which is referred as the 8B × 3H × 11H cuboid. Two other cuboids, 28B × 3H × 3H and 8B × 5H × 7H, were designed similarly. Other length combinations such as B16−S32, B16−S36, and B37−S37 were also tried for 7B × 7H × 9H (B16−S32 and B16−S36), 5B × 9H × 9H (B16−S32), and 5B × 5H × 7H 8201

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Figure 3. Three-dimensional origami with BLCS. (A−C) Schematic diagrams (perspective view is shown in A, and two side views are shown on the top panels of B and C) and corresponding transmission electron microscope (TEM) results (bottom panels of B and C) of the 8B × 3H × 11H cuboid. Inset in the bottom panel of B shows an averaged TEM micrograph: (D) 28B × 3H × 3H rod; (E) 8B × 5H × 7H cuboid; (F) 5B × 5H × 7H (B37−S37) cuboid; (G) 7B × 7H × 9H (B16−S32) cuboid; (H) 7B × 7H × 9H (B16−S36) cuboid. TEM images match the corresponding side views above. Scale bars: 50 nm. Full-size TEM images and native agarose gel electrophoresis analysis are shown in Figures S8−S14.

(B37−S37) cuboids (Figure 3 and section 1.2 in the Supporting Information). Measurements of interhelical distances of 3-D structures show a trend similar to those of 2-D structures, and interhelical distance is positively related to block length (Table S2). It is also worth mentioning that the long structures (e.g., the 28B × 3H × 3H rod, the 22B × 11H rectangle, and the 44B × 5H rectangle) can substantially bend, as the terminal blocks are far apart and linked by a long segment of single-stranded scaffold. For the 28B × 3H × 3H rod as an example, besides the desired straight configuration, bent configuration resulted as a major population. The internal tension that arises from the random coiling of the linking single-stranded segment of the scaffold is believed to be the cause of bending, and when the single-stranded segment formed a duplex (or partial duplex) with complementary strands, such a bending problem was alleviated (Figure S13). Modular Modifications. We then rearranged modular blocks for structural diversification. When a group of connecting staples to bridge two neighboring blocks is replaced by a new group, structural translocation will be established. Simple examples of translocation include structures with offset or flipped blocks (Figure 4A,B and Figures S15−S17). When a new group of connecting staples is applied to omit a certain block (with the staples related to the block excluded), a structure of contracted dimension can be generated. Adding back the excluded staples can result in an extension to the original size (Figure S19). On the other hand, extra segments of

duplexes can be inserted as spacers between two neighboring blocks, and consequently, an extended structure can result (Figure 4C,D). When double-stranded insertions have gradient lengths between a pair of neighboring blocks, they can be joined with a bending angle (Figure 4E,F). We were able to tune the angle by changing the steepness of the gradients across helices based on the 22B × 11H rectangle. A particular steepness of gradients across helices at the bending site (an increment of 10/11 nt, 5/6 nt or 3/4 nt for every outer helix) corresponds to a specific bending angle (130 ± 7°, 150 ± 7°, or 157 ± 6°, N = 50; Figure S22). Similar to the disc structure presented earlier in this article (Figure 2C), we managed to implement increasingly steep gradients up to extreme deviation from natural conformation of B-form DNA. To make a series of bending modifications for multiple blocks, a ring-like structure based on the 22B × 11H rectangle (Figure 4G) and a hexagon based on the 28B × 3H × 3H rod (Figure 4H) was constructed. More sophisticated structural remodeling was implemented by combining structural modifications with multimerization. For example, a hexagon homotrimerized (Figure 4I) or homohexamerized (Figure 4J) by bent structure monomers modified from the 8B × 3H × 11H cuboid was constructed. Morphable Structures. The construction under the presented framework also leads us to discover the morphable nature of the resulting structures. A staple that binds to the scaffold continuously along the perimeter with two consecutive 8202

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Figure 4. Modular modifications of BLCS structures. (A) Translocation of 2-D structure (with offset blocks) derived from the 22B × 11H rectangle. (B) Translocation of 3-D structure (with flipped blocks) derived from the 8B × 3H × 11H cuboid. Gold nanoparticles depicted as yellow dots locate in the middle of the cuboid with flipped blocks instead of on the terminal side of the original cuboid. (C) Extended 2-D rectangle derived from the 22B × 11H rectangle. (D) Extended 3-D cuboid derived from the 8B × 5H × 7H cuboid. (E) Bent 2-D structure derived from the 22B × 11H rectangle. (F) Bent 3-D structure derived from the 8B × 3H × 11H cuboid. (G) 2-D ring-like structure with multiple bending sites derived from the 22B × 11H rectangle. (H) 3-D hexagon structure with multiple bending sites derived from the 28B × 3H × 3H cuboid. (A−H) Top, schematic diagrams; bottom, AFM or TEM images. (I,J) 3-D hexagon homotrimerized (I) or homohexamerized (J) by bent structure monomers. Left, schematic diagrams (bent structure monomers shown in solid color); right, TEM images. Red lines: insertion of DNA segments. Scale bars: 100 nm. Full-size AFM/TEM images and native agarose gel electrophoresis analysis are shown in Figures S16, S18, and S20−S27.

conformation S (red) directed 10B × 25H to form a fat rectangle, the displacement of this set of tie staples coupled with the addition of the other set of tie staples for conformation L (blue) lead to the formation of thin rectangle. A reverse from configuration L to S can be done by another round of displacement and tie staple inclusion (Figure 5F,G). The global conformational change relies on the connectivity of unit cells, so the propagation of conformational change can be terminated by interrupting continuous connectivity. We divided the 22B × 11H rectangle into two pieces linked by single-stranded segments, which served to break continuity. When a subset of tie staples for conformation S was added to the left piece and a subset of tie staples for conformation L was added to the right piece, the two pieces took the respective conformations and the entire structure took a T shape (Figure 5H). When the same treatment of tie staples applied to a structure of continuous connection, such a T shape was not produced (Figure 5I). In the last example, we demonstrate that the relative positions of two guest protein molecules (e.g., streptavidin) decorated on the surface of the 10B × 25H rectangle can change according to the conformational isomerization. The distance between the two streptavidin molecules was 31 nm with underlying structure in conformation S (Figure 5J) and such a distance changed to 77 nm when the underlying structure switched to conformation L (Figure 5K). This example is meant to clearly show the distance change of the two protein molecules between the conformations S and L, but the closest distance we can place two adjacent guest protein

domains can serve as a conformational tie to force the adoption of one of the two conformations locally. The local conformational changes can then propagate across the entire structure to collectively generate a global conformational change (Figure 5A). One of the two conformational isomers, whose scaffold route in short segmented blocks (conformation S; Figure 5A, left) or in long continuous stretches (conformation L; Figure 5A, right), is presented when a certain set of tie staples (red or blue) is applied to the 22B × 11H rectangle (Figure 5D,E). Similar conformational isomers are presented for the 10B × 25H rectangle when one of the two sets of the tie staples is available (Figure 5B,C). When neither set of tie staples is available, two conformational isomers coexist with a specific population distribution (Figures S28 and S29). Our results of conformational isomerization about the 22B × 11H rectangle without tie staples (Figure S29) are mostly in line with the modeling and experimental results from an earlier study about a single junction, in which junction conformation was not preferable and the two forms of “mesojunctions” (equivalent to conformations S and L) were roughly equally probable.23 However, in the case of the 10B × 25H rectangle without tie staples (Figure S28), conformation S is in a majority, although this conformation is slightly energetically unfavorable compared to conformation L. Mechanisms of such a preference are yet to be carefully investigated. The tie staples can also be added after basic origami structural formation to dynamically change conformation (Figure S34). We have demonstrated next that the global conformational change is reversible. While the inclusion of tie staples for 8203

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Figure 5. Morphable structures resulting from origami with BLCS. (A) Schematic diagram of conformational change for a BLCS structure. The inclusion of a specific set of tie staples (red or blue) results in conformation S (left) or L (right). Note that the junction conformation in the middle is only shown for illustrative purposes as such a conformation is not energetically favorable due to the lack of base stacking at the junction points. Instead, a mixture of two conformations is presented when tie staples are not available (Figures S28 and S29). The two conformations of the 10B × 25H rectangle are shown in (B) (conformation S) and (C) (conformation L), and the two conformations of the 22B × 11H rectangle are shown in (D) (conformation S) and (E) (conformation L). (F,G) Reversible conformational change of the 10B × 25H rectangle. One conformational isomer can change into the other one in two steps: displacement of a specific set of tie staples, and the inclusion of the other set of tie staples. Pink and purple strands serve to displace red and blue tie staples, respectively. Each AFM image shows the conformation reshaped from the other conformation after the treatment. (H) T-shaped structure based on the 22B × 11H rectangle (continuous connectivity is interrupted by single-stranded segments shown as dashed lines). (I) Broom-like structure based on the 22B × 11H rectangle. Note that interface of two patches of respective conformations can be any of the yellow lines. (J,K) 10B × 25H rectangle with two streptavidin molecules decorated in conformation S (J) or L (K). (B−K) Top, schematic diagrams; bottom, the corresponding AFM images. Scale bars: 100 nm. Full-size AFM images and native agarose gel electrophoresis analysis are shown in Figures S30−S33, S35, and S36.

size of a hybrid structure is not restricted by the scaffold, and the mechanical strength of a hybrid is as strong as a scaffolded origami. The construction of hybrid structures also blurs the boundary between scaffolded (from origami approach) and scaffold-free (from LEGO approach) structures. The basic structural elements are shared across two approaches, and patches from respective approaches constitute hybrid structures. At a conceptual level, the characteristic features can be implanted from one approach to the other. For example, the modular nature of structural components from the LEGO approach is perfectly demonstrated for the origami approach in this study. The in-depth integration of origami and LEGO approaches reveals vast hidden design space to construct structures of greater versatility.

molecules under the current scheme is 4 nm (conformation S) or 10 nm (conformation L). Such a precise distance manipulation sheds lights on enzyme engineering to obtain optimal catalytic efficiency with intermediates to be relayed among components of multienzyme complexes in a controllable fashion.24

CONCLUSIONS Compared to the conventional origami design scheme, in which a full set of staple strands are usually solely dedicated to a particular structure, it is only necessary to change a subset of component staple strands to make substantial modifications to an existing structure under the presented framework. As a consequence, the cost effectiveness to construct diverse structures of different shapes or patterns is greatly enhanced. At the same time, the modular architecture and standardized structural elements make the designing process much easier. As a consequence, we are able to meet major construction challenges to build sophisticated DNA origami structures rapidly and cost-effectively (among many basic structures, one of them is used in modular remodeling to form seven different shapes). Many resulting structures became hybrid structures partially scaffolded and partially scaffold-free as base pairing between staples was implemented in the system. The two types of architectures complement each other to produce structures that inherit the desirable features from both sides. For example, the

METHODS Sequence Design. The DNA sequences were generated by caDNAno, and DNA strands were synthesized by Bioneer Corporation (www.bioneer.com). Scaffold strand M13mp18 was used for the 2-D structures, and an M13-based vector of length 8064 bases (p8064)11 was used for the 3-D structures. Structural Self-Assembly. 50 nanomolar of every staple strand and 10 nM of scaffold strand were mixed in 0.5× TE buffer (5 mM Tris, 1 mM EDTA) with 10−30 mM MgCl2 (pH 8). The mixture was subjected to one of the thermal annealing protocols: (A) rapid ramp from 90 to 60 °C (5 min per °C) and slow cooling from 60 to 25 °C (25 min per °C); (B) rapid ramp from 90 to 60 °C (5 min per °C) and slow cooling from 60 to 10 °C (25 min per °C); (C) rapid ramp 8204

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ACS Nano from 90 to 60 °C (5 min per °C) and slow cooling from 60 to 10 °C (2 h per °C); (D) incubation at a specific temperature. Gel Electrophoresis and Purification. Annealed DNA samples were purified by agarose gel (1−2%) electrophoresis before AFM/ TEM imaging. Gels were run in 0.5× TBE buffer (45 mM Tris, 1 mM EDTA, 45 mM boric acid) with 10 mM MgCl2 and stained with SYBR safe (Thermo Fisher Scientific). Target bands were cut under blue light and crushed in Freeze’N Squeeze columns (Bio-Rad) and then directly subjected to centrifugation at 1000g for 3 min at 4 °C. AFM Imaging. The morphology of the DNA structures was characterized by AFM (Multimode 8, Bruker) in liquid ScanAsyst mode. A 5 μL droplet of sample (1−10 nM, purified or unpurified) and a 40 μL drop of 0.5× TE buffer with 10 mM MgCl2 were applied to a freshly cleaved mica surface. Next, 5−10 μL of supplemental 10 mM NiCl2 was added to increase the strength of DNA−mica binding if necessary. TEM Imaging. The morphology of 3-D structures was characterized by TEM. 1 mL of 2% aqueous uranyl formate was mixed with 5 μL of 5 M NaOH and centrifuged at 14 000g for 10 min to serve as the stain solution. A 3.5 μL droplet (2−10 nM) of purified sample was pipetted onto the glow-discharged, carbon-coated grid (Electron Microscopy Sciences) for 4 min and then wicked off and stained for 5 s with 3.5 μL of stain solution. The stain solution was then blotted off by filter paper and left on the grid to air-dry. The stained sample was analyzed on FEI Tecnai Spirit, operated at 120 kV at 26 000−63 000× magnification.

Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for providing the facility support in TEM imaging. This work is supported by National Natural Science Foundation of China (31570860), “Thousand Talents Program” Young Investigator Award and a startup fund from the Tsinghua University−Peking University Joint Center for Life Sciences to B.W., University Grants Council of the Hong Kong Government Earmarked Grant (16302415) to Y.M. and B.W., and Tongji University China 985 Grant to Y.M.

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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/acsnano.7b03187. Experimental details, Figures S1−S36, and Tables S1 and S2 (PDF) DNA sequence information (XLS)

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Bryan Wei: 0000-0003-2515-2409 Present Address ⊥

Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA. Author Contributions

Y.C. and R.C. contributed equally to this work. Y.C. designed the system, performed the experiments, analyzed the data, and wrote the paper. R.C. designed the system, performed the experiments, and analyzed the data. M.K. designed the system in a smaller scale and performed the preliminary experiments. Y.W. performed the experiments, analyzed the data, and wrote the paper. Y.M. supervised the study, analyzed the data, and wrote the paper. B.W. conceived, designed, and supervised the study, analyzed the data, and wrote the paper. Author Contributions #

The first two authors contributed equally.

Notes

The authors declare the following competing financial interest(s): A provisional patent has been filed based on this work.

ACKNOWLEDGMENTS We thank D. Yang and Y. Jin for technical assistance, and Y. Ke and R. Lakerveld for helpful discussions. We acknowledge the 8205

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