Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.
Synthetic channels and pores have been of increasing interest for their applications as antimicrobial agents, drug delivery, catalysts, and sensors. 1 Furthermore, the development of synthetic channels and pores that mimic porous proteins should contribute to a better understanding of the structure and function of natural transmembrane channels. 2 Here, we report a dendritic dipeptide that self-assembles into thermally stable helical pores. The helical pores are stable in phospholipid membranes and selectively transport water.There has been little progress in the area of synthetic water channels, pores, and transporters. 1 Natural channels such as Aquaporin selectively transport water through primarily hydrophobic pores. 2,3 Recently, water was shown to transport through hydrophobic nanotubes very efficiently. 4 Hydrophobic pore sizes of 13-20 Å transport water faster than diffusion models. 5 Protons are also translocated through hydrophobic pores via a Grotthusstype mechanism. 6 We have previously reported the dendritic dipeptide, (4-3,4-3,5)-12G2-CH 2 -Boc-L-Tyr-L-Ala-OMe, that self-assembles into helical pores in bulk, in solution, and in vesicles. 7 This dendritic dipeptide self-assembled into helical pores with a column diameter (D col ) of 71.3 Å and pore diameter (D pore ) of 12.8 ( 1.2 Å. These helical pores suffered from low thermal stability since at 22°C they were in dynamic equilibrium with the dendritic dipeptide. Further studies led to improvements in the stability of the helical pores by more complex strategies. 8 We decided to attempt the stabilization of helical pores through simple π-stacking interactions on the dendron periphery by replacing the benzyl group with a naphthyl group. This generated (6Nf-3,4-3,5)12G2-CH 2 -Boc-L-Tyr-L-Ala-OMe (1). 9 In the bulk state, 1 formed helical pores similar to previously reported dendritic dipeptides 7,8 with D col ) 82.3 Å and D pore ) 14.5 ( 1.5 Å (Figure 1) in the bulk state. D pore is within the range of sizes required to facilitate transport of water and protons. 4,5 Wideangle X-ray diffraction fiber patterns (Figure 1b and Supporting Information) showed strong 3.5 Å π-stacking interactions due to the naphthyl groups not seen in previous dendritic dipeptides. 7,8 Modifying the outer periphery from benzyl to naphthyl increased the melting temperature (T m ) in bulk from 95 to 139°C. Furthermore, 1 self-assembled into helical pores in organic solvents that mimic the aliphatic region of phospholipid membranes ( Figure 2a). The T m in solution and the molecular ellipticity were also higher compared to the benzyl dendritic dipeptide previously reported (T m ) 40 vs 22°C). 7 The enhanced stability of the pores formed from 1 allowed their improved assembly into phospholipid membranes (Figure 2b). The helical pores showed CD spectra when incorporated into vesicles similar to their solution spectra. Additionally, the helical pores did not disassemble at high temperatures. This improved stability is due to enhanced π-stacking interactions on their periphery a...
We describe the covalent post-modification of a hydrogen-bonded assembly with the subsequent formation of a potent transmembrane Na+ ion transporter. Olefin metathesis is used to cross-link all 16 guanosine subunits in a lipophilic G-quadruplex. The resulting unimolecular G-quadruplex folds in the environment of a phospholipid membrane and functions as a Na+ ion transporter as judged by fluorescence and 23Na NMR transport assays.
This paper presents results from a series of pulsed field gradient (PFG) NMR studies on lipophilic guanosine nucleosides that undergo cation-templated assembly in organic solvents. The use of PFG-NMR to measure diffusion coefficients for the different aggregates allowed us to observe the influences of cation, solvent and anion on the self-assembly process. Three case studies are presented. In the first study, diffusion NMR confirmed formation of a hexadecameric G-quadruplex [G 1](16)4 K(+)4 pic(-) in CD(3)CN. Furthermore, hexadecamer formation from 5'-TBDMS-2',3'-isopropylidene G 1 and K(+) picrate was shown to be a cooperative process in CD(3)CN. In the second study, diffusion NMR studies on 5'-(3,5-bis(methoxy)benzoyl)-2',3'-isopropylidene G 4 showed that hierarchical self-association of G(8)-octamers is controlled by the K(+) cation. Evidence for formation of both discrete G(8)-octamers and G(16)-hexadecamers in CD(2)Cl(2) was obtained. The position of this octamer-hexadecamer equilibrium was shown to depend on the K(+) concentration. In the third case, diffusion NMR was used to determine the size of a guanosine self-assembly where NMR signal integration was ambiguous. Thus, both diffusion NMR and ESI-MS show that 5'-O-acetyl-2',3'-O-isopropylidene G 7 and Na(+) picrate form a doubly charged octamer [G 7](8)2 Na(+)2 pic(-) 9 in CD(2)Cl(2). The anion's role in stabilizing this particular complex is discussed. In all three cases the information gained from the diffusion NMR technique enabled us to better understand the self-assembly processes, especially regarding the roles of cation, anion and solvent.
In this paper, we report on the formation and properties of a water-stabilized dimer comprising calix[4]arene-guanosine conjugate cG 2. The 1,3-alternate calixarene cG 2 was poorly soluble in dry CDCl(3) and gave an ill-resolved NMR spectrum, consistent with its nonspecific aggregation. The compound was much more soluble in water-saturated CDCl(3). Two sets of well-resolved (1)H NMR signals for the guanosine residues in cG 2, present in a 1:1 ratio, indicated that the compound's D(2) symmetry had been broken and provided the first hint that cG 2 dimerizes in water-saturated CDCl(3). The resulting dimer, (cG 2)(2).(H(2)O)(n)(), has a unique property: it extracts alkali halide salts from water into organic solution. This dimer is a rare example of a self-assembled ion pair receptor. The identity of the (cG 2)(2).NaCl.(H(2)O)(n)() dimer was confirmed by comparing its self-diffusion coefficient in CDCl(3), determined by pulsed-field gradient NMR, with that of control compound cA 3, an adenosine analogue. The dimer's stoichiometry was also confirmed by quantitative measurement of the cation and anion using ion chromatrography. Two-dimensional NMR and ion-induced NMR shifts indicated that the cation binding site is formed by an intermolecular G-quartet and the anion binding site is provided by the 5'-amide NH groups. Once bound, the salt increases the dimer's thermal stability. Both (1)H NMR and ion chromatography measurements indicated that the cG 2 dimer has a modest selectivity for extracting K(+) over Na(+) and Br(-) over Cl(-). The anion's identity also influences the association process: NaCl gives a soluble, discrete dimer whereas addition of NaBPh(4) to (cG 2)(2).(H(2)O)(n)() leads to extensive aggregation and precipitation. This study suggests a new direction for ion pair receptors, namely, the use of molecular self-assembly. The study also highlights water's ability to stabilize a functional noncovalent assembly.
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