Supramolecular control of structure and reactivity
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Nucleic acids can form a variety of three-dimensional structures through complex hydrogen bonds in different sequence contexts 16 , Remarkably, guanine-rich repetitive sequences tend to fold into a four-stranded structure called a G-quadruplex G4 , which contains stacked planar G-quartets shown in Supplementary Figure S1 To date, it has been proven that a significant proportion of eukaryotic genomes can be converted into G4 structures 19 , which were even visualized in human cells In particular, the G4 is capable of adopting multiple conformations Although G4 DNAs have been regulated by a variety of external stimuli 22 , 23 , it remains a challenge to control these structures in a reversible manner.
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Recently, photo-induced conformational changes of nucleic acids have been achieved We also reported the reversible light-control of a G4 structure using some azobenzene derivatives, such as Razo and Razo-s structures shown in Supplementary Figure S2 25 , However, the major drawback of the photo-induced process is the depth limit of the excitation beam in tissues and biological systems.
Therefore, it is important to develop new structure-switching strategies and we intend to utilize supramolecular interactions for this purpose. Recently, some significant advances have been made in developing supramolecular controllers For example, a supramolecular switch has been reported that can reversibly control the antibacterial activity of specific molecules on demand These synthetic systems usually depend on specific molecular recognition events between hosts and guests 29 , Cucurbit[n]uril CBn in Supplementary Figure S3 , a multimeric macrocyclic and barrel-shaped molecule comprised of glycoluril rings and methylene bridges 31 , represents an attractive host for supramolecular recognition due to its structural rigidity and ability to complex with a variety of guests Of the known CBn homologues, CB7 structure is shown in Supplementary Figure S3 has drawn particular attention because of its remarkable solubility in aqueous solutions 33 , CB7 can bind to the guests with high biocompatibility and specificity.
Importantly, it has been successfully used in many biological applications, such as fishing for plasma membrane proteins 35 , regulation of bioorthogonal catalysis in cells 36 and the fabrication of biomimetic systems Razo is capable of inducing the folding of flexible DNA into a rigid G4 structure Upon adding CB7, the steric crowding associated with the non-covalent CB7-Razo complex prevents the approximation and contact of Razo with the DNA and therefore leads to a topological transition from G4 to the unfolded state right-to-left direction in Figure 1A.
UV-VIS titrations, Proton nuclear magnetic resonance 1 H-NMR and molecular docking studies provide direct evidence that CB7 preferably locks and encapsulates the positively charged piperidines of Razo through host—guest interactions. More importantly, supramolecular switching of human telomere DNA has been successfully used to manipulate enzymatic reactions in a reversible and competitive manner.
The oligonucleotides were obtained from Invitrogen Shanghai, China. The excitation and emission wavelengths were set at and nm, respectively. The detection was performed at RT with a 1-cm path-length cell. Compounds Razo, Razo-s and CB7 were synthesized according to the previous literatures 25 , 26 , The bandwidth was 5 nm and the response time was 2 s.
All CD spectra were baseline-corrected for signal contributions from the buffer and were the average of at least two runs. The following procedure is similar to the above one wherein AM is added sequentially to the starting preparation prior to measurement of the CD spectra. The obtained spectra were zeroed at nm. The results full spectra as well as the plot of Abs nm as a function of the concentration of CB7 added were recorded. All spectra were baseline-corrected for the signal contributions from the buffer.
The ligand 0. Next, CB7 solid 0. Finally, the sample was centrifuged, and the supernatant of the mixture was collected and then analyzed. Next, AM 1. The signal assignments are based on the chemical shifts and intensity patterns. The aim of this study was to investigate the possible interactions between the ligand Razo and the receptor CB7 when they were bound to each other.
To obtain accurate results, all docking experiments were performed with the default parameters.
In general, it is worth mentioning that targeting supramolecular metal-based complexes to the desired site is essential to control off-target effects of the delivered chemotherapic agent, as well as to reduce the possible intrinsic systemic toxicity of the supramolecular metal-based drug delivery system. Rakuten Global Market. Supramolecular Entanglement from Interlocked Molecular Nanomagnets. Recently, Therrien and coworkers have synthesized an anthracene-based metalla-rectangle with the idea to improve the cell uptake of the photosensitizer anthracene [ 98 ]. Your list of the life and mages pumps irreducible to these protections and failures. During the past decade, increasing interest has been manifested in the design and synthesis of discrete metallo-supramolecular architecture for biomedical applications.
The molecular structure of Razo was prepared and the Mulliken atomic charges were computed using density functional theory DFT calculations with the B3LYP functional and the 6—31G d basis set in Gaussian09 program 39 , The geometry of Razo was optimized using the functional bp86 without geometry constraints and the lowest energy conformation was used for docking. This program uses the anchor and grows algorithm for flexible ligand docking. For docking, the box was generated using the CB7 binding site; the energetic grid was computed using the Grid module of the DOCK program with parameter file.
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The scoring in DOCK is based on the non-bonded terms of molecular mechanic force field. Dock predicts the correct binding mode of ligand in the binding site of receptor. During docking, the receptor CB7 was kept rigid and the ligand Razo was flexible.
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Snap binding energies were calculated and scored for each pose. Snap binding energy is the energy difference between the complex and the sum of the receptor and ligand energies. The final docked structure was fully optimized on the Gaussian09 software package using PM3MM method. Docking was performed on a Linux workstation Ubuntu This assay was performed according to previously reported protocols 46 , For this assay, human thrombin was prepared as a 0. Next, Itelo 2. For the CB7-induced inhibition assay, new parallel thrombin-Itelo-Razo samples the same recipe as above were then treated with various amounts of CB7 for 15 min and the activity was examined.
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For the AM-induced reactivation assay, the thrombin-Itelo-Razo-CB7 samples were treated with various amounts of AM for 15 min and the activity was examined. The excitation and emission wavelengths were both set to nm, and a 1-cm path-length cell was used. For the kinetic measurements, 0. Untreated thrombin was used as an internal standard. All data were normalized to this control and expressed as a percentage. The CB7 stock solution was prepared in aqueous solution. For this assay, human thrombin was prepared as 0. The regulator CB7 or AM was added to a new parallel thrombin sample the same recipe as above followed by a min incubation and the activity of this thrombin-regulator sample was examined and normalized to the activity of the above control sample.
The statistical analysis was performed using the SPSS In the present study, we aim to develop a supramolecular switch capable of modulating DNA structures and enzymatic reactions. Appropriate operator molecules are required to achieve our goal. On the basis of our previous studies 25 , 26 , Razo and Razo-s show excellent abilities to induce the formation of G4 structures and are therefore selected as the candidates.
Molecular modeling studies indicate that the quaternary ammonium groups of Razo are deeply involved in the observed G4 binding These bulky cations may fit into the CB7 cavity 28 , thus preventing their access to the DNA phosphate backbone. Therefore, a plausible model of a supramolecular switch is designed to manipulate G4 structures. Razo and Razo-s were synthesized as previously reported 25 , To prove the feasibility of our concept, h-Telo was tested as a model. CD is fast and allows comparative studies of DNA conformations in related conditions As in our previous study 25 , 26 , the addition of either Razo or Razo-s efficiently induced the conformational conversion of h-Telo from a single-stranded form into a parallel G4 structure, but there was no significant difference in the ability of these two molecules to induce G4 structures Supplementary Figure S4.
Then, we examined the influence of increasing amounts of CB7 on the topological states of h-Telo in the presence of G4 inducers. Importantly, Razo and Razo-s did fall into very distinct categories in response to CB7. The sequential addition of CB7 did not significantly influence the topology of h-Telo in the Razo-s sample, as reflected by the small changes in the shape and intensity of the CD bands Supplementary Figure S5.
In striking contrast to the Razo-s sample, the addition of CB7 decreased the band intensities of the Razo sample to a large extent, indicating that a large G4 deformation occurred Figure 2A.
Topics range from micelles performing catalytic reactions, active sites on heme proteins and synthetic control of oligonucleotide structures to design of proteins. Supramolecular Control of Structure and Reactivity. Andrew D. Hamilton (Editor). ISBN: April Pages. E-Book CAD $
On the basis of these results, the behavioral differences between Razo and Razo-s might be attributed to the difference in their side-arms Supplementary Figure S2. These findings raised an interesting possibility that CB7 specifically interacted with the positively charged piperidines of Razo, but not the N-trimethylethanaminium moieties of Razo-s. Supramolecular modulation of G4 Structures.
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The arrow indicates the change in CD absorbance upon the addition of CB7. The arrow indicates the change in CD absorbance upon the addition of AM. Subsequently, CB7 green inset arrow and AM red inset arrow were sequentially added to the same sample as indicated. After each addition, the solution was measured and the absorbance reading was shown in response to the input the third to fourteenth points. The error bars reflect the standard deviations. Having proved the efficient deformation of G4 under the influence of CB7, we anticipated that AM was able to generate active Razo and induce G4 reformation through supramolecular competition.
To prove this point, increasing amounts of AM were added to the above preparation containing the two-component Razo—CB7 system and further incubated before the CD spectra were measured. The representative data are shown in Figure 2B. On the basis of these results, AM is able to relieve CB7-driven suppression of Razo-induced G4 formation in a dose-dependent manner.
An excellent switch should be able to withstand repeated stresses and sustain good reversibility over multiple cycles of treatments. To test the switching properties of our supramolecular assembly, h-Telo was subjected to the Razo treatment, followed by the sequential addition of the regulator either CB7 or AM. After each addition, the mixture was incubated further before the CD spectra were collected. On the basis of our observations, the height of the CD band Figure 2C was significantly reduced by the excess CB7 relative to AM, and the observed spectrum Supplementary Figure S6 has almost exactly the same shape as that of the DNA alone, indicating the efficient deformation of G4.
Strikingly, the continual addition of AM produced an evident increase in the band intensity Figure 2C and Supplementary Figure S6 , indicating the switch to reformation of G4 by the presence of excess AM relative to CB7. Hence, this supramolecular switch can maintain reversible control of G4 by adjusting the concentrations of regulators on demand, which is indeed extremely easy to put into practice.
Not surprisingly, the regulator treatment could not convert the flexible h-Telo into the parallel G4 structure, as reflected by the absence of the characteristic CD absorption Supplementary Figure S8. These results clearly indicated that there was no direct interaction between the regulator and the different DNA structures. Therefore, the above structure-switching of DNA is attributable to supramolecular competition between Razo and AM for binding to CB7, but is not based on the interaction between the DNA and the regulator itself.
On the basis of the above results, it is reasonable to assume that supramolecular complexation between CB7 and Razo is responsible for the CB7-driven deformation of G4.