Programmed pH-Driven Reversible Association and Dissociation of

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Programmed pH-Driven Reversible Association and Dissociation of Inter-Connected Circular DNA Dimer Nanostructures Yuwei Hu, Jiangtao Ren, Chun-Hua Lu, and Itamar Willner Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.6b01891 • Publication Date (Web): 26 May 2016 Downloaded from http://pubs.acs.org on May 28, 2016

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Programmed pH-Driven Reversible Association and Dissociation of Inter-Connected Circular DNA Dimer Nanostructures Yuwei Hu, Jiangtao Ren, Chun-Hua Lu, and Itamar Willner* Institute of Chemistry and The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

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Abstract:

The switchable pH-driven reversible assembly and dissociation of inter-locked circular DNA dimers is presented. The circular DNA dimers are inter-connected by pH-responsive nucleic acid bridges. In one configuration, the two-ring nanostructure is separated at pH = 5.0 to individual rings by reconfiguring the interlocking bridges into C-G•C+ triplex units, and the two-ring assembly is re-formed at pH = 7.0. In the second configuration, the dimer of circular DNAs is bridged at pH = 7.0 by the T-A•T triplex bridging units that are separated at pH = 10.0, leading to the dissociation of the dimer to single circular DNA nanostructures. The two circular DNA units are, also, inter-connected by two pH-responsive locks. The pH-programmed opening of the locks at pH = 5.0 or pH = 10.0 yields two isomeric dimer structures composed of two circular DNAs. The switchable reconfigured states of the circular DNA nanostructures are followed by time-dependent fluorescence changes of fluorophore/quencher labeled systems, and by complementary gel electrophoresis experiments. The dimer circular DNA structures are further implemented as scaffolds for the assembly of Au nanoparticle dimers exhibiting controlled spatial separation.

Keywords: nanotechnology, nanoparticle, switch, triplex, fluorescence

Recent advances in DNA nanotechnology included the development of stimuli-responsive interlocked circular DNAs (catenane) that undergo triggered transitions across dictated states.1 Two-,1e three-,2 five-3 and seven-rings4 DNA catenanes were reported. Triggers such as fuel/antifuel strands, pH, and metal ions/ligand (e.g. Hg2+-ions/cystamine), were used to reversibly switch the interlocked rings across the different states.5 Different supermolecular interlocked


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catenane devices such as a pH-driven pendulum,6 a three-state rotor5 of controlled clockwise/anti-clockwise directions and switchable catalytic DNAzyme were reported. Also, the triggered reconfiguration of interlocked DNA rings was implemented to control the structures of different-sized Au NPs and to control plasmonic surface-enhanced fluorescence properties of Au/fluorophore

conjugates.3,7

Sequence-specific

nucleic

acids

undergo

pH-driven

reconfigurations. For example, cytosine-rich nucleic acids undergo reversible random-coil (pH = 7.2)/i-motif (pH = 5.0) transitions.8 Similarly, triplex nucleic acids composed of bridging CG•C+ bridges (pH = 5.0) that undergo transition to C-G duplex structures (pH = 7.0), or T-A•T bridges (pH = 7.0) that dissociate to T-A duplexes at pH > 9.0, are well established.9 The pHstimulated formation and dissociation of triplex DNA structures were recently implemented to develop

supermolecular

DNA

devices,10

and

to

assemble

DNA-based

switchable

hydrogel/solution transitions.11 Here we wish to report on the assembly of pH-responsive supermolecular circular DNA nanostructures that undergo reversible pH-induced separation and reassembly. By interlinking of the two rings by two pH-responsive C-G•C+ and T-A•T units, the programmed separation of the structures into two different two-ring reconfigured structures is demonstrated, mimicking the Magic Chinese Linking Rings. The pH-driven release of a circular DNA carrying predesigned nucleic acids provides a general paradigm for the pH-induced intracellular release of nucleic acids, e.g. Si-RNA. We further demonstrate that the pH-responsive bridged two-ring systems allow the programmed assembly and separation of different sized Au NPs. Figure 1(A) depicts the composition of the pH-responsive two-ring bridged system being unlocked to the single circular DNAs, R1 and R2, via the pH-induced formation of the C-G•C+ triplex. The sequence L1 bridges the rings R1 and R2. The ring R1 is rigidified by the sequences


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C1 and F1, whereas ring R2 is rigidified by the strands C2 and F2. To follow the reversible pHstimulated separation and reassembly of the two rings, the strand C1 is modified at its 5′ end with the fluorophore Alex Fluor 647 (AF647 is insensitive to pH within a wide pH range,12 see Figure S1, supporting information), while the strand L1 is functionalized at its 3′ end with the quencher Iowa Black RQ-Sq (IAbRQ). At pH = 7.0, the bridging strand L1 forms a duplex with the two rings leading to the dimer R1-R2, where the intimate contact between the fluorophore and quencher leads to effective quenching of AF647. The base-sequence encoded in L1 results in, at pH = 5.0, the formation of the triplex C-G•C+ structure that is associated with ring R2, leading to the separation of the two rings R1, R2. The separation of the two rings leads to the activation of the fluorescence of the fluorophore. The subsequent neutralization of the system, pH = 7.0, separated the C-G•C+ triplex, resulting in the reassembly of the structures R1-R2 and the quenching of the fluorophore in the system. By the cyclic switching of the system between the values 5.0 and 7.0, the system is reconfigured between the two-rings and individual separated rings, respectively, followed by the fluorescence intensities of the fluorophore label, Figure 1(B). The pH-responsive bridged two-ring system being stabilized by T-A•T triplex bridges that dissociate at pH = 10.0 is depicted in Figure 2(A). The rings R1 and R2 are bridged by the nucleic acid L2 functionalized at its 3′ end with the quencher Iowa Black FQ (IAbFQ). The strand L2 forms a duplex with ring R2 and a second domain that forms in the presence of the auxiliary strand, L3, the triplex T-A•T structure with ring R1. The ring R1 is further rigidified with the fluorophore Alex Fluor 488 (AF488 is insensitive to pH,12 see Figure S1, supporting information) modified strand F3 and the strand C2 while ring R2 is rigidified with the strands F2 and C2. In the supermolecular dimer structure of the rings, the fluorophore AF488 is quenched due to the spatial proximity between the fluorophore and the quencher. Subjecting the system to


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pH = 10.0 dissociates the T-A•T triplex, resulting in the formation of the two separated rings R1 and R2, leading to the intensified fluorescence of AF488. By the cycling treatment of the system at pH = 7.0 and pH = 10.0, the reversible switching of the system between the dimer and monomer rings and accompanying low and high fluorescence of AF488 is demonstrated, Figure 2(B). Complementary PAGE electrophoresis experiments confirm the formation of the two ring dimers, and their pH-stimulated separation shown in Figure 1(A) and Figure 2(A) (for the results and accompanying discussion, see Figure S2, supporting information). The two rings R1 and R2 were further interlinked by two pH-responsive bridges, Figure 3(A). The ring R1 is functionalized with the AF647-modified strand C1 through hybridization, the fluorophore AF488 labeled strand F3, and the hybridization of strand L3 (that cooperatively stabilizes the T-A•T triplex). The ring R2 was functionalized through hybridization with the ligands L1, where the 3′ end of L1 is modified with the quencher IAbRQ, and L2, where the 3′ end of L2 is modified with the quencher IAbFQ, and further rigidified via hybridization by the strand C2 and the strand F2. The interaction of the two rings yields a two-site linkage of the two rings where the two domains of strand L1 form duplexes with the complementary domains of R1 and R2, respectively (leading to one inter-ring bridging site), and the domain of L2 form the TA•T triplex (with R1) and a duplex with R2 (leading to the second inter-ring bridging site). Note that the inter-ring strand is capable of stabilizing an intra-strand C-G•C+ triplex at pH = 5.0. Accordingly, Figure 3(A) depicts the programmed cyclic inter-conversion the two rings across three two-ring configurations. At pH = 7.0, the two rings are interlinked through the two bridging sites, state I, resulting in the quenching of the two fluorophore labels AF647 and AF488. Subjecting state I to pH = 5.0 results in the reconfiguration of strand L1 into the C-G•C+ triplex structure, a process that opens state I to form the single bridge L2 linked dimer of the two


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rings R1-R2, state II. In turn, treatment of state I at pH = 10.0 dissociates the L2-stabilized T-A•T triplex bridging units, leading to the open of two rings configuration bridged by the L1 strand, state III. In this configuration the fluorescence of F3 (AF488) is triggered on. Furthermore, subjecting state III to pH = 5.0 results in the dissociation of the L1 bridging site (through the formation of the C-G•C+ triplex), and the concomitant formation of the L2 bridging site transforming state III (high fluorescence of AF 488, F3) to state II (high fluorescence of AF647, C1). The different pH-stimulated transitions between state I, II and III are reversible. Figure 3(B) depicts the fluorescence changes of the system upon transition across the states I→II→I→III→II→III→II→III→I. The formation of the two-ring supermolecular structure in state I was further supported by PAGE electrophoresis experiments, see Figure S3 (supporting information). The pH-responsive inter-linked circular DNA nanostructures were further used to assemble dimers of different sized Au NPs and to induce their separation into single nanoparticles, Figure 4. Au NPs, 5 nm and 10 nm, modified with single nucleic acids A1 and A2, respectively, were used to functionalize the different bridged pH-responsive circular DNA structures. In Figure 4(A) the dimers R1-R2 are produced by linking the appropriate domains with the linker L10, including the encoded information to yield at pH = 5.0 a C-G•C+ triplex stabilized structure that leads to the separation of the rings. The two rings R1 and R2 are further rigidified by hybridization with the strand C2. Figure 4(B), panel I, shows representative STEM images of the resulting dimers. By imaging the large-areas of the particles (Figure S4), we estimate the yield of the dimer structures to be ca. 70%. The average distance, d1, separating the NPs is ca. 12 nm, Figure 4(B), panel II. Even though the circular DNA system exhibits structural flexibility, the estimated distance separating the NPs fits well with the calculated distance taking into account


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the diameters of the rings and a planar configuration of the rings (d1 ≈ 15 nm). Treatment of the dimer structures of the AuNPs-functionalized DNA rings at pH = 5.0 separates the structure to single Au NPs, yield 96%, Figure S5. Similarly, Figure 4(C) depicts the AuNPs-functionalized R1-R2 circular DNA dimer, crosslinked by the T-A•T pH-responsive strand L20. The rings are inter-connected with the strand L20 that includes complementary domains to yield the T-A•T triplex stabilized bridging site on R1 (in the presence of the auxiliary strand L3), and a second bridging domain that generates, through hybridization, a duplex with ring R2. The ring R1 is modified through hybridization with the 5 nm-sized Au NP modified with A1 strand and ring R2 is functionalized, via hybridization, with the 10 nm-sized Au NP modified with strand A2. The two-ring structures are further rigidified by their hybridization with the strand C2. At pH = 10.0, T-A•T triplex dissociates, leading to the separation of the Au NPs dimer into individual Au NPs. Figure 4(D), panel I, shows representative dimers of the Au NPs associated with the T-A•T crosslinked circular DNAs. By analyzing large areas domain of the resulting dimer Au NPs, we estimate their yield to be ca. 60-65%, Figure S6. The average distance separating the nanoparticles, d2, is estimated to be ca. 6 nm, Figure 4(D), panel II. As expected, the interparticle distance is smaller as compared to the Au NPs dimer displayed in Figure 4(A). The calculated inter-particle distance, taking into account a planar geometrical arrangement of the two rings suggests an interparticle distance of ca. 6.6 nm, consistent with the experimental value. Treatment of the dimer structures of the AuNPs-functionalized DNA rings at pH = 10.0 separates the structure to single Au NPs, yield 97%, Figure S7. In conclusion, the study has demonstrated the assembly of inter-connected pH-responsive tworing DNA systems that undergo pH-induced switchable dissociation and association processes. Specifically, we implement triplex C-G•C+ or T-A•T bridging units as the function components


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to separate and associate the two-ring structures. By the appropriate design, we have constructed an overlapping two-ring DNA systems linked together by two pH-responsive inter-ring locks. The programmable, switchable and reversible pH-induced selective unlocking of each of the locks yields two different open isomer structures of the two rings. The pH-induced separation of a circular DNA carrying predesigned nucleic acids provides a means to stimulate the intracellular release of nucleic acid inhibitors, e.g. Si-RNA. Finally, the pH-responsive inter-connected tworing systems provided scaffolds for the organization of different sized Au NPs dimer structures of controlled interparticle distance. The switchable pH-induced separation and reassembly of the NPs dimers were demonstrated. Experimental Section. The DNA strands used in this study are summarized as follows: (R1) 5′AGC ACT TCA CAT ATG AGT ACG GAG GGA CAG TAT GGA CAG GGA CTA GCT TCT CTA CTC GAT TCT GAT TCT TTT CTT TTC TTT TCT TAC CGT ATG GAG ACA G3′; (R2) 5′-AGC ACT TCA CGC TCG GGA GGG GAG GGG AGG ACT ACT ACA CTG CAG CAC TGG ACC ACG ATC TTC GTA TGA TCA ACG ACA TAT GAC AGC ATT GGG AGA CAG-3′; (C1) 5′-Alexa Fluor 647-ATG TGA AGT GCT CTG TCT CC-3′; (F1) 5′-AGA GAA GCT AGT CCC TGT CC-3′; (L1) 5′-CCT CCC CTC CCC TCC CTT TGC CTC CCC TCC CCT CCG TAC TC-Iowa Black RQ-3′; (F2) 5′-CGT GGT CCA GTG CTG CAG TG-3′; (C2) 5′-GAA GTG CTC TGT CTC C-3′; (L2) 5′-GTC ATA TGT CGT TGA TCA TAA TGT AGT TCT TTT CTT TTC TTT TCT T-Iowa Black FQ-3′; (F3) 5′-Alexa Fluor 488-AGA ATC GAG TAG AGA AGC TAG TCC CTG TCC-3′; (L3) 5′-AAG AAA AGA AAA GAA AAG AA-3′; (A1) 5′-HSCGA AGA AGA GAA GCT AGT CCC TGT CC-3′; (A2) 5′-HS-CCA GCG CGT GGT CCA GTG CTG CAG TG-3′; (L10) 5′-CCT CCC CTC CCC TCC CTT TGC CTC CCC TCC CCT


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CCG TAC TC-3′; (L20) 5′-GTC ATA TGT CGT TGA TCA TAA TGT AGT TCT TTT CTT TTC TTT TCT T-3′. (Colored sequences overlap the colored domains in the respective figures). The synthesis and purification of the individual rings and their assembly into pH-responsive circular DNA dimers are provided in the supporting information. Also the synthesis and purification of the single nucleic acid functionalized Au NPs are described in the supporting information. The dynamic association and dissociation of inter-connected DNA dimers (200 nM) were probed in HEPES buffer solution (10 mM, pH 7.0, MgCl2 20 mM). The pH-driven reversible association and dissociation of the inter-connected circular DNA dimers were triggered by diluted acetic acid and ammonium hydroxide solution, to pH 5.0 and pH 10.0, respectively. The fluorophores Alexa Fluor 647 (AF647) and Alexa Fluor 488 (AF488) were excited at λ = 650 nm and λ = 494 nm, respectively. ASSOCIATED CONTENT Supporting Information. Experimental materials, the synthesis and purification of the DNA rings, the PAGE electrophoresis images of the inter-connected circular DNA dimer and the dissociation of the dimer to single circular DNA nanostructures, representative STEM images of the inter-connected circular DNA-AuNPs nanostructures. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * [email protected]


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This research is supported by the Israel Science Foundation and by the Minerva Center for Complex Biohybrid Systems. REFERENCES (1)

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Figure 1. (A) Switchable pH-stimulated assembly and dissociation of a two circular DNA structure using C-G•C+ triplex-responsive crosslinker. (B) Switchable fluorescence intensities observed upon the pH-induced reconfiguration of the two circular DNAs between the dimer configuration, state I, and individual separated rings, state II.


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Figure 2. (A) Switchable pH-stimulated assembly and dissociation of a two circular DNA structure using T-A•T triplex-responsive crosslinker. (B) Switchable fluorescence intensities observed upon the pH-induced reconfiguration of the two circular DNAs between the dimer configuration, state I, and individual separated rings, state II.


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Figure 3. (A) Programmed pH-stimulated dissociation and association of a two circular DNA construct crosslinked by two pH-responsive locks, state I, being reconfigured to different isomeric dimer structures, state II and state III. Treatment of state I at pH = 5.0 yields state II, whereas treatment of state I at pH = 10.0 generated state III. Subjecting state II to pH = 10.0 or of state III to pH = 5.0 induced reversible transition between the states. All three states can be reversibly inter-converted across the different states by implementing appropriate pH values. (B) Switchable fluorescence intensities observed upon the pH-stimulated transitions between the states I→II→I→III→II→III→II→III→I.


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Figure 4. (A) Switchable pH-stimulated formation and dissociation of dimeric Au NPs (5 nm and 10 nm) using the pH-responsive C-G•C+ two-ring DNA scaffold. (B) STEM images corresponding to the dimer structures associated with the two circular DNA scaffold bridged by the C-G•C+-responsive linker, panel I (scale bar 25 nm), and statistic interparticle distance analysis of the Au NPs dimers, panel II. (C) Switchable pH-stimulated formation and dissociation of dimeric Au NPs (5 nm and 10 nm) using the pH-responsive T-A•T two-ring DNA scaffold. (D) STEM images corresponding to the dimer structures associated with the two circular DNA scaffold bridged by the T-A•T-responsive linker, panel I (scale bar 25 nm), and statistic interparticle distance analysis of the Au NPs dimers, panel II.


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Table of Contents


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Programmed pH-Driven Reversible Association and Dissociation of

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