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Structural DNA Nanotechnology State of the Art and Future
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Journal of the American Chemical Society Perspective. Figure 1 Structural foundations of structural DNA nanotechnology and representative examples each panel described left to right Seeman s. original proposals to use immobile DNA junctions to create self assembling arrays A 6 and self assembled 3D DNA lattices B as sca olds to. organize macromolecules into crystalline lattices 6 C DNA nanostructure motifs used to create periodic 2D arrays and 3D crystal top helical. structures of the motifs bottom AFM images of the assembled 2D arrays and optical image of the 3D crystal double crossover DNA tile 13 4 4. DNA tile 14 6 4 DNA tile 15 and tensegrity triangle DNA tile 16 D Polyhedral DNA nanostructures molecular models of a DNA cube 21 DNA. tetrahedron 22 DNA dodecahedron 23 and DNA biprism 24 E Algorithmic self assembly based on double crossover tiles Sierpinski triangles28 and. binary counter 29 F DNA origami nanostructures top schematic drawings of the structures bottom corresponding AFM or TEM images 2D. DNA origami smiley face 32 3D DNA origami in the shape of a gear 37 curved single layer 3D origami in the shape of a vase 38 and DNA origami. gridiron 114 G Complex nanostructures produced using the single stranded DNA tile strategy 45 46 Images reproduced with permission C ref 13. 1998 Nature Publishing Group NPG ref 14 2003 American Association for the Advancement of Science AAAS ref 15 2006 American. Chemical Society ACS ref 16 2009 NPG E ref 28 courtesy of P Rothemund ref 29 2005 ACS F ref 32 2006 NPG ref 37 2009 AAAS. ref 38 2011 AAAS ref 114 2013 AAAS and G ref 45 2012 NPG ref 46 2012 AAAS. 11199 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 2 Representative dynamic DNA nanostructures A DNA tweezer based on DNA strand displacement technique 48 B Autonomous DNA. walker catalyzed by metastable DNA hairpin fuel 63 C Movement of DNA spider on a predescribed landscape 62 D DNA assembly line DNA. walker will transport gold nanoparticles to a di erent product formation station with instructions from DNA strand displacement 66. More recently Yin and co workers synthesized a variety of the nal product resulting in eight possible outcomes. 1D 44 2D 45 and 3D46 DNA nanostructures from single Recently researchers demonstrated that DNA walkers can. stranded DNA tiles SSTs The platform that they developed also be used to mediate multistep organic synthesis 67 pointing. is based on a series of interlocking local connections between to the possibility of programming chemical reactions with. SSTs Collections of SSTs form 2D sheet or 3D block canvases dynamic DNA nanodevices. that can be selectively engraved to create di erent shapes 2 3 Applications of Structural DNA Nanotechnology. and patterns by simply including or omitting speci c SSTs As structural DNA nanotechnology transitions from adoles. Figure 1G cence into adulthood the need to demonstrate potential. 2 2 Dynamic DNA Nanodevices Natural biological applications is of the utmost importance We must improve our. devices are designed to operate in dynamic conditions ability to engineer and program complex molecular systems and. responding to subtle biological cues to realize their functions prove that designer DNA nanostructures can be employed in. The structural properties of DNA that allow it to serve as a real world applications If we continue to exploit the. versatile construction material have been exploited to create programmability of DNA nanostructures to accurately template. dynamic nanodevices Figure 2A ranging from small switch functional molecules materials and probes we will be able to. able structures47 52 and recon gurable systems53 58 to organize these external elements into practical devices and. structures that display complex movements such as rolling 59 engineer molecular sensors circuits and actuators. rotating 60 and walking 61 67 Inorganic nanomaterials such as quantum dots nanowires. Protein molecular motors transform chemical energy into and nanorods and metal nanoparticles have attracted much. mechanical energy to facilitate a variety of biological functions attention because of their unique optical and electronic. from cell division transport and motility to enzymatic activity properties that can be used in solar cells phototransistors. DNA nanotechnologists have long envisioned programming laser diodes light emitting diodes and other optoelectronic. DNA walker molecules to mimic the ability of natural motor devices 68 However a better understanding of the photo. proteins to walk along intracellular tracks and achieve physical behavior of these materials is necessary to use them in. controlled motion Imparting directionality to DNA walkers such devices Researchers have successfully used DNA. could be realized by means of successively additng DNA fuels nanosca olds to organize metallic nanoparticles semiconductor. by coordinating conformational changes between di erent nanocrystals69 74 Figure 3A and organic chromophores75. components of the walker by leading the walker through into well de ned architectures These hybrid DNA nanostructure. selective track modi cations or by pairing their motion to complexes have enabled systematic investigation of distance. unidirectional reaction cycles Researchers have already dependent interactions between photonic elements 76 78 In one. demonstrated unidirectional motion by DNA walkers through example Liedl and co workers constructed a spiral nanoscale. prescribed tracks63 65 and landscapes62 Figure 2B C On the staircase on which gold nanoparticles were arranged at regular. basis of this technology it is possible to develop walkers that intervals and with chiral geometries72 Figure 3A This work. are programmed to travel a certain path by encoding the demonstrates how DNA sca olding can be used to control the. directions into the nucleotide sequences of the walker itself and precise structural arrangement of metal nanoparticles enabling. into the corresponding landscape For example Seeman s group researchers to tailor surface plasmon resonance and the inter. reported a DNA based robot that manufactured structures on a action with visible light In another example DNA nanostruc. nanoscale assembly line66 Figure 2D Their DNA walker tures were used to organize various organic chromophores into. traveled through three xed modules that were individually arti cial light harvesting complexes with control over cascading. programmed to selectively incorporate a gold nanoparticle into unidirectional energy transfer 75. 11200 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 3 Representative examples of DNA nanostructure directed assembly of inorganic and protein molecules top schematics bottom. corresponding TEM or AFM images A Left to right gold nanoparticles organized by a 2D DNA tile array 69 gold nanorod dimers with controlled. angles between the nanorods organized by DNA origami 70 DNA origami directed quantum dot architectures 71 and DNA origami directed gold. nanoparticles in a chiral arrangement and the induced circular dichromic e ect 72 B Left to right Organization of streptavidin proteins by a 2D. DNA nanoarray 14 protein arrays templated by a 2D DNA nanostructure through aptamer protein interactions 79 and orthogonal Snap tag and. His tag mediated decoration of DNA origami 80 Images reproduced with permission A ref 69 2006 ACS ref 70 2011 ACS ref 71 2012 ACS. ref 72 2012 NPG and B ref 14 2003 AAAS ref 79 2007 ACS ref 80 2010 Wiley. As we previously mentioned one of the initial goals of RNA nanosca olds for spatial organization of metabolic elements. structural DNA nanotechnology was to use 3D DNA lattices as for hydrogen production 83 Willner and co workers organized a. hosts to organize guest protein molecules and facilitate protein glucose oxidase and horseradish peroxidase enzyme cascade by 2D. crystallography Although this vision has yet to be realized DNA lattices 85 More recently Yan and co workers conducted. scientists have already begun to use DNA nanostructures as substrate channeling in a multienzyme cascade by using an. chaperones to align and organize protein molecules using arti cial DNA swinging arm 87. di erent strategies including ligand protein such as biotin DNA origami sca olds have also been used to organize. streptavidin interactions 14 aptamer target interactions 79 and motor proteins and study their spatially dependent motility88. ligand engineered tagged protein interactions80 Figure 3B Figure 4B Understanding how motors cooperate produc. Shih and co workers recently designed DNA origami nanotube tively and compete antagonistically is important for under. liquid crystals to provide the appropriate alignment environ standing how intracellular transport is regulated Researchers. ment for determining the previously unknown structure of a recently demonstrated this molecular tug of war by displaying. membrane protein by nuclear magnetic resonance NMR 81 di erent numbers of dynein and kinesin motor proteins from a. Turber eld and co workers used periodic 2D DNA tile DNA origami structure 89 By controlling the number distance and. arrays as templates to arrange proteins and subsequently used orientations of the two types of biological motors they were able. cryo EM to solve their structures 82 to systematically study coordinated motor behavior Figure 4C. Proteins some of Nature s most powerful agents are large Structural DNA nanotechnology has also emerged as a useful. macromolecules that perform a wide assortment of functions tool for biological and medicinal applications Figure 5 The. required to sustain life including metabolic catalysis DNA intrinsic biocompatibility nanoscale dimensions programm. replication and molecular transport In order to better ability and ability for functionalization of DNA nanostructures. understand the governing dynamics in complex protein are virtually unrivaled by existing techniques In particular the. systems we need control over the number orientation and addressable con guration of DNA origami lends itself to. arrangement of the constituents Nucleic acid sca olds a ord detection of gene expression90 and single nucleotide poly. this level of control and researchers have already used RNA morphism 91 The Sugiyama group developed DNA origami. and DNA platforms to engineer a number of enzyme frames and rulers to investigate biomolecular interactions such. cascades83 87 Figure 4A For example Silver and co workers as protein DNA binding events and homologous recombination. used a bacterial host to transcribe RNA and assemble intracellular processes in real time at the single molecule level92 94 Figure 5A. 11201 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 4 Representative examples of DNA nanostructure directed assembly of protein molecules for functional structures A Upper left assembly. and disassembly of holoenzymes mediated by DNA strand displacement 84 upper right glucose oxidase yellow and horseradish peroxidase red. enzyme cascade organized by 2D DNA lattices 85 lower left substrate channeling in a multienzyme cascade by an arti cial DNA swinging arm 87 and. lower right glucose oxidase yellow and horseradish peroxidase red enzyme cascade organized on DNA origami with distance control 86 B. Rectangular DNA origami travels on a cellular actin network through the binding and action of myosin lever arms 88 C Molecular tug of war. between two motor proteins displayed from a 12 helix DNA bundle 89. Further the spatial addressability and multivalent properties of molecules More recently Amir et al showed that DNA origami. DNA nanostructures make them promising vehicles for targeted robots can dynamically interact with each other and perform. drug delivery For example Douglas and co workers demon logic computations in a living animal opening up opportunities. strated a barrel shaped nanorobot that releases Fab antibody to develop smart theranostic nanodevices99 Figure 5E. fragments in the presence of target cells 95 In their system two. ssDNA aptamer locks are opened by speci c markers present on 3 FRONTIERS OF STRUCTURAL DNA. the surface of cells Figure 5B After opening the payload NANOTECHNOLOGY. molecules inside the barrel are exposed inducing a particular. cellular signaling pathway Anderson and co workers used a DNA The interdisciplinary nature of DNA nanotechnology crosses. tetrahedron to deliver small interfering RNA in vivo to target and the traditional boundaries of physics chemistry biology and. suppress gene expression in a mouse model96 Figure 5C engineering and allows scientists to connect and integrate their. Programmable DNA nanostructures have also been used as unique perspectives in pursuit of solutions to the most pressing. synthetic vaccine platforms 97 98 Yan Chang and co workers problems in medicine technology and more From the earliest. used a DNA tetrahedron to coassemble model antigens and DNA junction motifs to the most recently developed DNA. CpG adjuvants into nanoscale complexes with precise control of nanostructures of incredible complexity the eld has started to. the valency and spatial arrangement of each component98 explore various novel applications including directed material. Figure 5D Tests on immunized mice demonstrated that assembly structural biology biocatalysis DNA computing nano. antigen adjuvant DNA complexes induced stronger and robotics disease diagnosis and drug delivery as we mentioned. longer lasting antibody responses against the antigen without brie y in the previous section Each of these applications is made. stimulating a reaction to the DNA nanostructure itself as possible by the ability of DNA nanostructures to direct molecular. compared to an unstructured mixture of antigen and CpG species with nanoscale precision while maintaining the utmost. 11202 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 5 Biological applications of DNA directed assembly A DNA origami frames to investigate protein DNA binding events in real time at the. single molecule level 92 B Barrel like DNA nanorobot programmed to be open in the presence of target cells and expose Fab antibody fragment. cargo 95 C Six siRNA duplexes and folic acid tags gray chaperoned by a DNA tetrahedron are injected into mice the tetrahedra bind to tumor. cells by targeting folate receptors expressed on the tumor cell surface 96 D DNA tetrahedron adjuvant antigen vaccine complex CpG ODN. adjuvant molecules curved yellow ribbons and the model streptavidin antigen red bind speci cally to B cells and are subsequently presented to T. cells to activate B cell response and antibody production 98 E Three di erent drugs carried by a DNA nanorobot can be released in a programmed. fashion by undergoing complex DNA computation in a living cockroach 99 Image E reproduced with permission from ref 99 2014 NPG. structural integrity DNA nanotechnology is progressing with We have divided the remaining outlook into three main. such incredible speed that it is becoming more and more di cult areas Design and Assembly which will include discussions of. to predict from which areas the next breakthroughs will occur dynamic developmental quasicrystal lattice 3D periodic crystal. Next we are merely providing our opinion about the critical lattice sca olded surface mediated algorithmic and topolog. challenges that the eld faces and which directions we believe ical assembly Future Applications which will include. researchers should pursue to help structural DNA nano discussions of structural DNA nanotechnology for molecular. technology reach its full potential sca olds sensors robotics and computing and From Nano to. 11203 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 6 Schematic illustrations of A dynamic DNA self assembly with simultaneous joining in one end and dissociation in the other end B. developmental DNA self assembly in which the assembly process may grow into di erent nal products in response to di erent external cues C. an example of a possible quasicrystal 2D penrose tiling using DNA tile self assembly and D self replication of DNA nanostructures. Angstrom Technology in which we conceive of potential di erent DNA building blocks could be exploited to mimic. directions the eld might explore over the longer term dynamic instability where polymerization of exible DNA tiles. 3 1 Design and Assembly 3 1 1 Dynamic Assembly can be induced through seeded growth on a rigid tile and. George Whitesides once wrote Although much of current depolymerization of the exible tiles can be initiated by. understanding of self assembly comes from the examination of removing the rigid tile protection cap When the association. static systems the greatest challenges and opportunities lie in and dissociation reactions reach equilibrium the input of. studying dynamic systems Perhaps the most important additional rigid tiles will catalyze the polymerization of released. justi cation for studying self assembly is its central role in exible tiles Studying the association and dissociation kinetics. life 100 Dynamic self assembly processes underlie many forms of model DNA tile species with variable exibility is absolutely. of adaptive and intelligent behaviors in natural systems essential to recreating this or similar dynamic self assembling. however very little is known about the principles that govern systems. them One of the most intriguing dynamic self assembly 3 1 2 Developmental Assembly The creation of new life. processes in living cells is the polymerization of cytoskeletal depends on a set of extraordinary developmental processes. biopolymers such as microtubules Microtubule polymerization including stem cell growth di erentiation and morphogenesis. is characterized by two unique phenomena referred to as tread These processes rely on Nature s ability to precisely control the. milling101 and dynamic instability 102 Tread milling is said to spatial and temporal relationship between cellular components. occur with the net addition of tubulin monomers at one end of and signaling pathways It would be extremely interesting if we. the microtubule and simultaneous net loss of tubulin at the could create synthetic DNA systems that mimic this kind of. opposite end Dynamic instability is characterized by switching spatiotemporal development DNA tiles have the potential to. between phases of relatively slow and rapid shortening of the develop into unique patterns through instructions embedded in. microtubules at their ends Although these phenomena were the building blocks or by external stimuli such as fuel strands. once thought to be incompatible it is now known that both that trigger new growth pathways Figure 6B Metastable. behaviors coexist in near steady state conditions in cells 101 102 DNA nanostructures could be designed and used to serve as. It would be quite interesting if we could use the desirable nucleation seeds and or catalysts to increase the growth and. properties of DNA nanostructures to recapitulate these development of particular pathways Multivalency and or. phenomena and ultimately dissect the governing dynamics of cooperativity within DNA nanostructures could be exploited. microtubule polymerization Figure 6A DNA tiles could be for nucleation and initiation of alternative assembly paths. designed such that the rate of assembly equaled the rate of Researchers have already begun implementing certain aspects. disassembly resulting in steady state tread milling and xed of developmental assembly For example Pierce and co workers. length nanotubes Further if tiles with bi or tridirectional recently reported the dynamic assembly of DNA nanostruc. growth were utilized the resulting arrays would have de ned tures through a seeded cascade of hybridization chain reactions. shapes The intrinsic conformational exibility and rigidity of based on toehold mediated strand displacement 103 Strand. 11204 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. displacement circuits have also been used to trigger DNA tile potential to improve the quality of DNA crystals but has yet to. assembly and control their growth into DNA tubes 104 There be exploited for crystallization applications. are several key challenges to implementing toehold mediated Reducing the volume of solvent present in the lattice cavities. strand displacement in dynamic DNA systems including by inserting sequence speci c binding proteins may improve. leakage slow reaction rates and the necessity for high salt the di raction quality but sequence independent methods to. conditions Researchers are currently tying to address each of orient proteins within the DNA cavities still need to be. these problems Zhang and co workers reportedly designed developed This strategy is particularly attractive as some have. toehold exchange probes and optimized the speci city of DNA already demonstrated that RNA binding proteins are useful. hybridization so that their system can detect single base chaperones for RNA crystallization Piccirilli and co workers. changes 105 Designing robust self assembling DNA platforms derived RNA speci c antibodies using synthetic phage display. to mimic developmental systems will also certainly require a libraries and showed that the antibody fragments promoted. thorough understanding of the thermodynamics and kinetics of crystallization of RNA molecules 112 Similarly DNA tile. DNA self assembly binding antibodies could be identi ed through in vitro evolution. 3 1 3 Quasicrystal Lattice Assembly In 2011 the Nobel and used for coassembly of the DNA units and proteins into. Prize in Chemistry was awarded to Dan Shechtman for his designed 3D crystals. discovery of quasicrystals a nding that fundamentally changed Recent developments in free electron laser FEL X ray. how chemists understand solid matter Prior to his report 106 nanocrystallography have the potential to revolutionize the eld. scientists believed that the atoms in a crystal were always of structural biology by providing highly focused coherent. packed into symmetric patterns that repeated periodically We X ray beams with a peak brilliance that is 109 higher than the. have since come to understand that it is possible to form X ray beams at the most powerful synchrotron facilities 113. packed crystals from nonrepeating patterns an arrangement of Obtaining high quality di raction patterns using FEL X ray. molecules now referred to as quasicrystalline The distinctive requires micrometer sized nanocrystals it might be possible to. properties of quasicrystals as well as their unique structures program the growth of 3D DNA lattices into nite nanocrystals. have intrigued scientists ever since their discovery 106 108 with suitable dimensions by designing a 3D box that acts as a. however very little is currently known about the properties sca old to nucleate the growth of a periodic lattice of DNA. exhibited by synthetic and naturally occurring quasicrystals tiles Growing 3D crystals with designed crystal morphologies. Scientists have yet to determine what guides quasiperiodic and dimensions is undoubtedly an interesting topic in itself. rather than periodic growth and what factors result in the 3 1 5 Sca olded Assembly The development of sca olded. unique properties that quasicrystals display 109 110 One of DNA origami represents a milestone in structural DNA. the biggest challenges facing researchers today is the lack of nanotechnology 32 While the complexity and robustness of. plausible systems from which to assemble quasicrystals and 2D and 3D DNA origami objects has increased over the past. enable further studies DNA platforms are promising candidates few years researchers still lack basic understanding of the. for the controlled programmable growth of synthetic thermodynamics and kinetics of sca olded assembly Under. quasicrystals Figure 6C Interacting DNA building blocks standing the minutia of DNA origami formation will allow us to. can potentially be programmed to assemble into 2D and 3D guide the design of more complex DNA nanostructures. quasicrystal patterns allowing us to investigate the still optimize annealing protocols and manipulate functionalized. unknown mechanisms of quasicrystal growth and providing a DNA nanostructures more e ectively Structurally speaking we. means to organize other materials for engineering pursuits are still a long way from being able to weave a sca old strand. 3 1 4 Periodic 3D Crystal Lattice Assembly Realizing 3D along arbitrary paths within a DNA origami structure although. DNA lattices as hosts to organize guest protein molecules and some progress has been made in this direction Recently Yan. facilitate protein crystallography necessitates that 3D DNA and co workers developed a novel strategy to fold gridiron like. crystals can themselves be reliably assembled and characterized DNA origami structures 114 In that work interconnected four. Researchers successfully demonstrated the assembly of a 3D arm junctions were used as vertices within a network of DNA. DNA crystal in which the triangular unit tiles were connected fragments and measured distortion of the junctions from. by sticky ends and solved its structure to 4 resolution using relaxed conformations allowed the sca old strand to traverse. X ray crystallography 16 However most DNA crystals only through individual vertices in several directions Despite this. di ract to 7 10 leaving scientists trying to determine why initial success interlacing the sca old strand through the. rationally designed DNA crystals do not di ract with better vertices of multiarm junctions remains a challenge that if. resolution There are several possible explanations including achieved would dramatically improve our ability to form. defects that arise during crystallization impurities in the aperiodic tiling patterns and polyhedral 3D structures using the. synthetic DNA and the presence of bulky solvent molecules DNA origami technique Besides increasing complexity scaling. in the large cavities of the DNA lattices up the size of DNA origami and reducing the cost of staple. Crystal defects may be caused by the limited rigidity of DNA strand synthesis are also important issues facing DNA. unit motifs where any over or under twisting of the tiles nanotechnologists Various strategies to address these limi. causes inter tile mismatches that are detrimental to the integrity tations have been explored including the use of longer single. of the crystal lattice We surmise that imparting exibility to stranded sca olds 42 double stranded sca olds 115 origami of. certain domains of the DNA building blocks may allow the unit origami super origami 41 and enzymatic production of staple. tiles to more reliably accommodate their neighbors and reach a strands on microarray chips 116 which has the added bene t of. lower energy state for crystal lattice formation thereby improving greater delity than chemical synthesis Researchers are. the overall quality of the crystal The Sleiman group pioneered relentlessly pushing forward to achieve more robust DNA. DNA junctions with metal complex modi cations that combine origami technology. rigidity within the core of the junction with intrinsic exibility in 3 1 6 Surface Mediated Assembly DNA origami has. the arms 111 This type of modi ed DNA unit motif has the shown great success in directing the assembly of nanoelectronic. 11205 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. and photonic elements and has been used as a lithographic within cells Molecular topology is a fascinating and technically. mask to etch nanoscale patterns on silicon and graphene challenging topic that DNA nanotechnology is ideally suited to. substrates 117 For practical device applications it is highly examine Seeman and co workers were the rst to show that. desirable to achieve robust patterning of self assembled DNA topological structures such as knots and Borromean rings could. nanostructures on inorganic surfaces and several groups have be self assembled from DNA by combining right handed B. developed unique strategies to organize DNA origami form and left handed Z form DNA together to create positive. nanostructures on solid substrates 118 120 The next logical and negative nodes 125 Yan and co workers later used the DNA. step is to generate chemically functional surface features to origami method to construct Mo bius strip topological. facilitate patterning of DNA origami nanostructures into structures that could be recon gured into catenanes and. spatially addressable arrays Surface mediated assembly may twisted topological ribbons through toehold mediated strand. be the key to scaling up DNA nanostructure assemblies into displacement 56 More recently Willner and co workers. wafer size arrays Researchers have already shown that mica and developed strategies to interlock DNA rings into multiring. silicon dioxide surfaces will mediate the assembly of small DNA catenanes 126 Weizmann and co workers just reported the. tiles into millimeter range periodic 2D lattices 121 The bu er assembly of complex knots and links by speci cally con guring. conditions especially the concentration and species of the ions four way DNA junctions 127 Despite these interesting examples. present may play a critical role in surface mediated di usion of the area of DNA based topological nanostructures is under. DNA nanostructures an important factor that remains to be developed compared to the geometric structures that have been. explored 122 It would also be interesting to use uidic 2D reported over the past decade New construction strategies and. surfaces such as lipid bilayers to improve the surface mediated topological targets should be identi ed to push the frontiers of. di usion of DNA nanostructures 123 DNA based molecular topology forward. 3 1 7 Algorithmic Assembly In mathematics and computer 3 1 9 Self Replicating DNA Nanostructures Self replication. science an algorithm describes a set of simple instructions for is an astounding process by which a molecule in a dynamic. solving a problem However if you look beyond their system makes an identical copy of itself Biological cells. traditional context in mathematics you will see that algorithms provided they have a suitable environment reproduce by cell. can be used to describe the process of self assembly in the division During cell division linear DNA autonomously. natural world Consider the self assembly of lipids into undergoes replication by enzyme mediated processes and is. membranes or viral proteins into capsids or even just amino transmitted to o spring It is a considerable challenge to design. acids into intricately folded protein structures each process and construct autonomous structures that mimic the action of. involves the spontaneous or automatic assembly of small nucleic acid polymerases and are capable of replicating entire. components into larger more complex structures The process synthetic DNA systems nonenzymatically Figure 6D The. by which these structures grow can be described as algorithmic rst development in this direction was reported by Seeman s. In each example a limited number of molecular building blocks group in 2011 128 They constructed a seven tile seed and. grow into higher order structures by following the growth rules successfully generated several generations of progeny in a step. encoded into the building blocks themselves DNA tiles are by step manner Winfree and co workers recently showed that. information rich building blocks ideally suited for implement mechanically induced scission of 2D DNA crystals can. ing algorithmic self assembly Originally proposed by Winfree accurately replicate self assembled DNA nanopatterns by. algorithmically self assembled DNA nanostructure patterns creating new fronts of crystal growth 129 However constructing. have been experimentally demonstrated For example Winfree autonomous self replicating systems that do not require. and co workers showed that DNA double crossover tiles could external manipulation remains a signi cant challenge Pierce. be programmed to compute and grow into Sierpinski triangle28 and co workers demonstrated autocatalytic DNA duplex. and binary counter assemblies 29 They also showed that formation by way of a cross catalytic circuit 63 yet extending. prescribed DNA origami displaying sticky end capture probes this concept to independent formation of sophisticated DNA. function as e ective nucleation seeds to grow algorithmic arrays nanopatterns needs additional development. while suppressing spurious nucleation which is a major source 3 2 Future Applications The successful design and. of errors during algorithmic assembly 124 The design of novel assembly of the DNA nanosystems discussed above will. nucleation frames could improve the delity and robustness undoubtedly lead to many new opportunities and innovative. of algorithmic assemblies of DNA tiles Other errors arise applications The information rich character of self assembling. from sticky end mismatches between di erent tiles that share DNA nanostructures in particular will create many new. certain sticky end sequences The kinetics of tile tile association frontiers for the application of designer DNA nanostructures. between the algorithmic building blocks should be carefully as molecular sca olds sensors computers and robots In. investigated to promote the desired computations and reduce the following sections we will discuss the potential of DNA. any undesirable mismatches Also tile sets could be expanded nanostructures to serve as sca old for functional nanoelectronic. beyond the typical double crossover DNA tiles to more complex and nanophotonic devices to regulate protein interactions and. or optimal geometries to facilitate multivalent and cooperative to create sense compute actuate elements for molecular. binding between the tiles and allow for improved understanding medicine However these examples are in no way limiting. of the constraints that limit the scope of algorithmic assembly and the eld has already demonstrated a tendency to grow in. 3 1 8 Topological DNA Nanostructures In biological unexpected directions surprising even the sagest of researchers. systems there is a clear relationship between the speci c 3 2 1 Molecular Sca olds for Nanophotonics or Nano. structure of a biomolecule and its function In particular electronics One of the most obvious applications of a DNA. biopolymers are important molecules whose structure supports nanostructure is to direct the assembly of other less. the organization and functionality of cells The topology of controllable materials as was discussed in the previous sections. biopolymers can be exploited to facilitate tasks such as packing We have seen several examples of spatially addressable DNA. information bearing DNA molecules into tiny compartments origami structures being used to organize nanoelectronic and. 11206 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. photonic components However we have not yet seen concrete. examples of DNA nanostructures in functional nanoelectronic. and photonic devices where bottom up DNA directed, assembly is interfaced with top down lithographic methods. of micro and macroscale patterning The latest developments. in surface mediated self assembly and site speci c control of. chemical properties could enable more precise arrangement of. these nanophotonic or nanoelectronic elements into regular. large scale patterns that can be integrated with macroscopic. 3 2 2 Molecular Sca olds for Enzyme Cascades DNA, directed assembly of complex protein arrays is another area of. development to watch for in the future Enzymes marvels of. natural evolution are intramolecular organizations of proteins. that are capable of recognition capture and activation of. molecules and regulation of biochemical processes These protein. complexes act as the central functional components of metabolism. and reproduction in living systems 130 The binding sites for. substrates and cofactors are chemically speci c while the active. sites are stereospeci c and highly sensitive to conformational. rearrangement Inspired by Nature researchers have pursued a. variety of strategies to regulate and control the catalytic activities of. enzymes as well as to understand the mechanism of enzyme. function and pathways 131 135 Compared to most conventional. techniques DNA nanotechnology is a highly e cient and. controllable strategy to achieve structural programmability and. recon gurability through rational design and construction. Assembling enzymes and cofactors on DNA nanostructure. sca olds has already allowed researchers to probe the essential. parameters for modulating catalysis such as intermolecular Figure 7 Illustration of potential applications of DNA nano. distance and relative spatial position 85 87 136 138 One example technology A Programming biochemical pathways with controlled. of controlling the activity of an individual enzyme using DNA input and output B Design and implementation of theranostic. was reported in 2013 where the authors achieved mechanical nanodevices on targeted cell surfaces that carry out functions such as. regulation of the enzyme luciferase by attaching a DNA compute sense release signal trigger activation and deliver. spring 139 In the same year a DNA tweezer actuated enzyme therapeutic molecules across the cell membrane. nanoreactor was successfully constructed 140, An even loftier and more valuable goal is to engineer highly the eld of personalized medicine A smart molecular doctor. programmed cascading enzyme pathways on DNA nanostruc would have the same responsibilities as a real human doctor. ture platforms with control of input and output sequences including diagnostic and therapeutic roles but would operate. Achieving this goal not only would allow researchers to mimic entirely at the cellular level Directly treating individual diseased. the elegant enzyme cascades found in Nature and attempt to cells to cure them on the single cell level o ers improved. understand their underlying mechanisms of action but also therapeutic e ciency and fewer side e ects since smaller drug. would facilitate the construction of arti cial cascades that do doses are required compared to conventional therapies. not exist in Nature Figure 7A Other targeted drug delivery systems based on multifunc. One major challenge in integrating multiple proteins into tional liposomes polymersomes and nanoparticles have already. DNA nanostructures is to precisely de ne their relative been developed 141 DNA is an attractive material for theranostic. orientation and position A set of reliable and general methods applications not only because of its inherent design modularity. for site speci c conjugation of proteins with oligonucleotides structural programmability and biocompatibility but also because. must be established in order to accommodate the diversity of DNA molecules of a particular sequence or with certain. proteins of interest In an ideal system a single protein with modi cations can selectively bind distinguish and communicate. multiple coupling sites would be conjugated to unique DNA with target cells to trigger drug release Researchers have made. sequences to enable absolute orientational control of the protein strides toward constructing DNA based drug containers and. relative to the DNA nanostructure In this way the active sites of DNA nanostructures that can be embedded into lipid bilayers 142. the enzymes in a multienzyme cascade for example could be particularly after the establishment of the DNA origami method. precisely oriented to facilitate substrate intermediate product The rst DNA origami box with a responsive lid that recognized. transfer and the overall enzymatic activity of the cascade could a speci c oligonucleotide key and subsequently opened was. be optimized reported in 2009 34 More recently researchers developed a DNA. 3 2 3 Molecular Sense Compute Actuate Devices A far nanobarrel with two single stranded aptamer locks that were. reaching goal of structural DNA nanotechnology is to develop opened by the presence of target cells in vitro 95. smart molecular machines that perform sense compute Performing DNA computation directly on the surface of. actuate mechanisms based on intrinsically information rich cells or in cellular environments will facilitate in vivo targeting. DNA molecules and structures Figure 7B For example the and drug release Recently Rudchenko Stojanovic and. development of smart molecular doctors would revolutionize colleagues engineered DNA strand displacement cascades that. 11207 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society Perspective. Figure 8 From nano to angstrom level control engineering molecular toolboxes composed of DNA RNA peptide and protein molecules and. their unnatural derivatives to extract new design rules and create complex self assembling structures with angstrom level spatial control. detected the presence of certain cell markers on the surface of nanostructures rather than by thermal annealing under high. cells 143 In another report Hemphill and Deiters successfully magnesium concentrations 154 155. engineered oligonucleotide logic gates to detect speci c 3 3 From Nano to Angstrom Technology Living cells. microRNA inputs in live mammalian cells 144 As more complex are information rich sophisticated machines that display. and robust DNA based computing systems are developed it angstrom level organizational precision Although DNA nano. may be possible to integrate them into cellular systems to structures are exquisitely programmable they are only able to. control and trigger cellular functions such as gene expression or regulate biological molecules at a relatively coarse level compared. to interfere with the metabolic pathways 145 Recently researchers to Nature If we want additional control we must push the. reported the construction of a consensus network that boundaries of nanoscale fabrication to the angstrom level In. distinguishes between two di erent input signals and reports contrast to DNA RNA and proteins have more re ned. the majority signal 146 By combining DNA computation based architectures with angstrom level features These aspects of. target cell detection with recon gurable DNA based drug their organization have attracted increasing attention in the past. containers it may be possible to create a DNA nanorobot that decade For example several rationally designed RNA nano. can interface and communicate with living cells Figure 7B structure have been constructed 156 157 Methods for engineering. There are a number of critical issues that must be addressed designed proteins and nanostructured complexes using proteins. before DNA nanorobots can be used for drug delivery in vivo have also begun to emerge 158 159 The progress of characterization. Researchers must nd a way to protect DNA nanostructures techniques such as cryo EM X ray di raction and NMR supports. from degradation by the intra and extracellular nucleases and the development of angstrom technology In particular the most. liver metabolism over long periods Compact DNA nanostruc recent developments in cryo EM techniques allow crystallization. tures generally display relative stability against DNA nucleases free structural determination of large sized proteins that is. for a short time a few hours 147 148 In the future it will be comparable to X ray methods 160 161 Using DNA origami frames. important to increase resistance to biodegradation by using both as structural hosts and as references the structure of DNA. methods such as chemical cross linking of selected DNA and RNA binding proteins may now be determined to angstrom. strands or designated DNA backbone modi cations Identifying level resolution by cryo EM 162 This advance will provide. the mechanisms by which DNA nanostructures enter cells researchers with atomic level structural information in con. without being damaged and escape endosomal processing 149 is junction with the structural solutions obtained from X ray. also a critical point Other issues such as immunogenicity150 crystallography that can be fed back into the design pipeline. and tissue distribution should also be considered elevating the eld to unimaginable heights Figure 8. The biggest obstacles to transforming DNA nanostructures In summary after more than 30 years of growth structural. from mere curiosities into real world solutions are the cost of DNA nanotechnology is transitioning from adolescence into. synthetic DNA small production scales typically low yield of adulthood The eld is crossing the boundaries of physics. complex 3D structures and sensitivity of DNA to ionic chemistry biology and engineering and is poised to generate. strength temperature and nucleases Researchers have already unique approaches and solutions to real world challenges in. begun to address these issues by optimizing origami design and science and technology In the next phase of structural DNA. folding strategies to increase assembly yields151 and shorten nanotechnology novel interactions between DNA RNA and. assembly times152 and by developing suitable puri cation proteins could be used to facilitate angstrom technology. strategies for large scale synthesis 153 It is also important to representing the major challenges and opportunities in. develop biocompatible conditions for e ciently folding DNA molecular design assembly computing and programming. 11208 dx doi org 10 1021 ja505101a J Am Chem Soc 2014 136 11198 11211. Journal of the American Chemical Society,Perspective. AUTHOR INFORMATION 27 Erben C M Goodman R P Turberfield A J J Am Chem. Soc 2007 129 6992 6993, Corresponding Author 28 Rothemund P W K Papadakis N Winfree E PLoS Biol.
hao yan asu edu 2004 2 2041 2053, Notes 29 Barish R D Rothemund P W K Winfree E Nano Lett. 2005 5 2586 2592,The authors declare no competing nancial interest. 30 Winfree E Bekbolatov R Lect Notes Comput Sci 2004 2943. ACKNOWLEDGMENTS 31 Sahu S Reif J H Algorithmica 2010 56 480 504. The authors acknowledge nancial support from NSF ARO 32 Rothemund P W K Nature 2006 440 297 302. 33 Ke Y G Sharma J Liu M H Jahn K Liu Y Yan H Nano. ONR NIH and DOE,Lett 2009 9 2445 2447, 34 Andersen E S Dong M Nielsen M M Jahn K Subramani. REFERENCES R Mamdouh W Golas M M Sander B Stark H Oliveira C L. 1 Aldaye F A Palmer A L Sleiman H F Science 2008 321 P Pedersen J S Birkedal V Besenbacher F Gothelf K V Kjems. 1795 1799 J Nature 2009 459 73 75, 2 Li H Y Carter J D LaBean T H Mater Today 2009 12 24 35 Douglas S M Dietz H Liedl T Hogberg B Graf F Shih. 32 W M Nature 2009 459 414 418, 3 Seeman N C Annu Rev Biochem 2010 79 65 87 36 Endo M Hidaka K Kato T Namba K Sugiyama H J Am.
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