Hydrogen‐Bonding‐Mediated Vesicular Assembly of Functionalized Naphthalene–Diimide‐Based Bolaamphiphile and Guest‐Induced Gelation in Water

This paper describes the spontaneous vesicular assembly of a naphthalene–diimide (NDI)‐based non‐ionic bolaamphiphile in aqueous medium by using the synergistic effects of π‐stacking and hydrogen bonding. Site isolation of the hydrogen‐bonding functionality (hydrazide), a strategy that has been adopted so elegantly in nature, has been executed in this system to protect these moieties from the bulk water so that the distinct role of hydrogen bonding in the self‐assembly of hydrazide‐functionalized NDI building blocks could be realized, even in aqueous solution. Furthermore, the electron‐deficient NDI‐based bolaamphiphile could engage in donor–acceptor (D–A) charge‐transfer (CT) interactions with a water‐insoluble electron‐rich pyrene donor by virtue of intercalation of the latter chromophore in between two NDI building blocks. Remarkably, even when pyrene was located between two NDI blocks, intermolecular hydrogen‐bonding networks between the NDI‐linked hydrazide groups could be retained. However, time‐dependent AFM studies revealed that the radius of curvature of the alternately stacked D–A assembly increased significantly, thereby leading to intervesicular fusion, which eventually resulted in rupturing of the membrane to form 1D fibers. Such 2D‐to‐1D morphological transition produced CT‐mediated hydrogels at relatively higher concentrations. Instead of pyrene, when a water‐soluble carboxylate‐functionalized pyrene derivative was used as the intercalator, non‐covalent tunable in‐situ surface‐functionalization could be achieved, as evidenced by the zeta‐potential measurements.     

Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas

The development of large synthetic ligands could be useful to target the sizeable surface areas involved in protein–protein interactions. Herein, we present long helical aromatic oligoamide foldamers bearing proteinogenic side chains that cover up to 450 Ų of the human carbonic anhydrase II (HCA) surface. The foldamers are composed of aminoquinolinecarboxylic acids bearing proteinogenic side chains and of more flexible aminomethyl-pyridinecarboxylic acids that enhance helix handedness dynamics. Crystal structures of HCA-foldamer complexes were obtained with a 9- and a 14-mer both showing extensive protein–foldamer hydrophobic contacts. In addition, foldamer–foldamer interactions seem to be prevalent in the crystal packing, leading to the peculiar formation of an HCA superhelix wound around a rod of stacked foldamers. Solution studies confirm the positioning of the foldamer at the protein surface as well as a dimerization of the complexes.     

Novel Coronene–Naphthalene Dimide‐Based Donor–Acceptor Pair for Tunable Charge‐Transfer Nanostructures

Charge‐transfer (CT) assemblies of aromatic donor (D) and acceptor (A) molecules have recently gained attention as a promising material for organic electronics and ferroelectrics. Two major factors which govern their functions are the strength of CT interaction and their supramolecular nanostructuring. Here we present coronene‐naphthalenediimide (NDI)‐based novel D‐A pairs that form alternately stacked CT assemblies. Through systematic substitution of the NDI derivatives and studying their CT interactions with coronene, a clear understanding of the secondary forces responsible for controlling their association is gained. Finally, the use of CT‐based supramolecular amphiphiles for their nanostructural engineering into ordered one‐dimensional (1‐D) assemblies is demonstrated.     

Hydrogen‐Bonding Induced Alternate Stacking of Donor (D) and Acceptor (A) Chromophores and their Supramolecular Switching to Segregated States

This paper reports comprehensive studies on the mixed assembly of bis‐(trialkoxybenzamide)‐functionalized dialkoxynaphthalene (DAN) donors and naphthalene‐diimide (NDI) acceptors due the cooperative effects of hydrogen bonding, charge‐transfer (CT) interactions, and solvophobic effects. A series of DAN as well as NDI building blocks have been examined (wherein the relative distance between the two amide groups in a particular chromophore is the variable structural parameter) to understand the structure‐dependent variation in mode of supramolecular assembly and morphology (organogel, reverse vesicle, etc.) of the self‐assembled material. Interestingly, it was observed that when the amide functionalities are introduced to enhance the self‐assembly propensity, the mode of co‐assembly among the DAN and NDI chromophores no longer remained trivial and was dictated by a relatively stronger hydrogen‐bonding interaction instead of a weak CT interaction. Consequently, in a highly non‐polar solvent like methylcyclohexane (MCH), although kinetically controlled CT‐gelation was initially noticed, within a few hours the system sacrificed the CT‐interaction and switched over to the more stable self‐sorted gel to maximize the gain in enthalpy from the hydrogen‐bonding interaction. In contrast, in a relatively less non‐polar solvent such as tetrachloroethylene (TCE), in which the strength of hydrogen bonding is inherently weak, the contribution of the CT interaction also had to be accounted for along with hydrogen bonding leading to a stable CT‐state in the gel or solution phase. The stability and morphology of the CT complex and rate of supramolecular switching (from CT to segregated state) were found to be greatly influenced by subtle structural variation of the building blocks, solvent polarity, and the DAN/NDI ratio. For example, in a given D–A pair, by introducing just one methylene unit in the spacer segment of either of the building blocks a complete change in the mode of co‐assembly (CT state or segregated state) and the morphology (1D fiber to 2D reverse vesicle) was observed. The role of solvent polarity, structural variation, and D/A ratio on the nature of co‐assembly, morphology, and the unprecedented supramolecular‐switching phenomenon have been studied by detail spectroscopic and microscopic experiments in a gel as well as in the solution state and are well supported by DFT calculations.     

Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution

In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right‐handed and left‐handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer–protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 Å resolution and revealed a number of unanticipated protein–foldamer, foldamer–foldamer, and protein–protein interactions.     

Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

In Alzheimer’s disease, amyloid‐β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β‐sheet conformation, binds to the Aβ peptide hairpin‐stacked fibril through β‐sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four‐times higher than that of the natural product was identified.     

Porphyrin-naphthodiimide interactions as a structural motif in foldamers and supramolecular assemblies

pi-pi Stacking interactions between electron deficient naphthalenediimides (NDI) and electron-rich porphyrins (POR) leading to charge transfer are shown to be prevalent in linked NDI-POR and POR-NDI-POR structures. For flexibly-linked systems, intramolecular interactions lead to S-shaped foldamers in solution, whereas intermolecular association is predominant in more rigid systems. The foldamer structures can be interrupted by competing aromatic solvents, by six-coordination of metallated porphyrin derivatives, by protonation of the free base porphyrin in non-metallated structures, and in facially sterically hindered porphyrins.     

Biocatalytic Self‐Assembly of Supramolecular Charge‐Transfer Nanostructures Based on n‐Type Semiconductor‐Appended Peptides

The reversible in situ formation of a self‐assembly building block (naphthalenediimide (NDI)–dipeptide conjugate) by enzymatic condensation of NDI‐functionalized tyrosine ( NDI‐Y ) and phenylalanine‐amide ( F‐NH₂ ) to form NDI‐YF‐NH₂ is described. This coupled biocatalytic condensation/assembly approach is thermodynamically driven and gives rise to nanostructures with optimized supramolecular interactions as evidenced by substantial aggregation induced emission upon assembly. Furthermore, in the presence of di‐hydroxy/alkoxy naphthalene donors, efficient charge‐transfer complexes are produced. The dynamic formation of NDI‐YF‐NH₂ and electronic and H‐bonding interactions are analyzed and characterized by different methods. Microscopy (TEM and AFM) and rheology are used to characterize the formed nanostructures. Dynamic nanostructures, whose formation and function are driven by free‐energy minimization, are inherently self‐healing and provide opportunities for the development of aqueous adaptive nanotechnology.     

Screening of pi-basic naphthalene and anthracene amplifiers for pi-acidic synthetic pore sensors

Synthetic ion channels and pores attract current attention as multicomponent sensors in complex matrixes. This application requires the availability of reactive signal amplifiers that covalently capture analytes and drag them into the pore. pi-Basic 1,5-dialkoxynaphthalenes (1,5-DAN) are attractive amplifiers because aromatic electron donor-acceptor (AEDA) interactions account for their recognition within pi-acidic naphthalenediimide (NDI) rich synthetic pores. Focusing on amplifier design, we report here the synthesis of a complete collection of DAN and dialkoxyanthracene amplifiers, determine their oxidation potentials by cyclic voltammetry, and calculate their quadrupole moments. Blockage experiments reveal that subtle structural changes in regioisomeric DAN amplifiers can be registered within NDI pores. Frontier orbital overlap in AEDA complexes, oxidation potentials, and, to a lesser extent, quadrupole moments are shown to contribute to isomer recognition by synthetic pores. Particularly important with regard to practical applications of synthetic pores as multianalyte sensors, we further demonstrate that application of the lessons learned with DAN regioisomers to the expansion to dialkoxyanthracenes provides access to privileged amplifiers with submicromolar activity.     

Role of Intramolecular Aromatic π–π Interactions in the Self‐Assembly of Di‐l‐Phenylalanine Dipeptide Driven by Intermolecular Interactions: Effect of Alanine Substitution

Although the role of intermolecular aromatic π–π interactions in the self‐assembly of di‐l ‐phenylalanine (l ‐Phe‐l ‐Phe, FF), a peptide that is known for hierarchical structure, is well established, the influence of intramolecular π–π interactions on the morphology of the self‐assembled structure of FF has not been studied. Herein, the role of intramolecular aromatic π–π interactions is investigated for FF and analogous alanine (Ala)‐containing dipeptides, namely, l ‐Phe‐l ‐Ala (FA) and l ‐Ala‐l ‐Phe (AF). The results reveal that these dipeptides not only form self‐assemblies, but also exhibit remarkable differences in structural morphology. The morphological differences between FF and the analogues indicate the importance of intramolecular π–π interactions, and the structural difference between FA and AF demonstrates the crucial role of the nature of intramolecular side‐chain interactions (aromatic–aliphatic or aliphatic–aromatic), in addition to intermolecular interactions, in deciding the final morphology of the self‐assembled structure. The current results emphasise that intramolecular aromatic π–π interaction may not be essential to induce self‐assembly in smaller peptides, and π (aromatic)–alkyl or alkyl–π (aromatic) interactions may be sufficient. This work also illustrates the versatility of aromatic and a combination of aromatic and aliphatic residues in dipeptides in the formation of structurally diverse self‐assembled structures.     

Hydrogen-Bonding Induced Alternate Stacking of Donor (D) and Acceptor (A) Chromophores and their Supramolecular Switching to Segregated States

This paper reports comprehensive studies on the mixed assembly of bis-(trialkoxybenzamide)-functionalized dialkoxynaphthalene (DAN) donors and naphthalene-diimide (NDI) acceptors due the cooperative effects of hydrogen bonding, charge-transfer (CT) interactions, and solvophobic effects. A series of DAN as well as NDI building blocks have been examined (wherein the relative distance between the two amide groups in a particular chromophore is the variable structural parameter) to understand the structure-dependent variation in mode of supramolecular assembly and morphology (organogel, reverse vesicle, etc.) of the self-assembled material. Interestingly, it was observed that when the amide functionalities are introduced to enhance the self-assembly propensity, the mode of co-assembly among the DAN and NDI chromophores no longer remained trivial and was dictated by a relatively stronger hydrogen-bonding interaction instead of a weak CT interaction. Consequently, in a highly non-polar solvent like methylcyclohexane (MCH), although kinetically controlled CT-gelation was initially noticed, within a few hours the system sacrificed the CT-interaction and switched over to the more stable self-sorted gel to maximize the gain in enthalpy from the hydrogen-bonding interaction. In contrast, in a relatively less non-polar solvent such as tetrachloroethylene (TCE), in which the strength of hydrogen bonding is inherently weak, the contribution of the CT interaction also had to be accounted for along with hydrogen bonding leading to a stable CT-state in the gel or solution phase. The stability and morphology of the CT complex and rate of supramolecular switching (from CT to segregated state) were found to be greatly influenced by subtle structural variation of the building blocks, solvent polarity, and the DAN/NDI ratio. For example, in a given D-A pair, by introducing just one methylene unit in the spacer segment of either of the building blocks a complete change in the mode of co-assembly (CT state or segregated state) and the morphology (1D fiber to 2D reverse vesicle) was observed. The role of solvent polarity, structural variation, and D/A ratio on the nature of co-assembly, morphology, and the unprecedented supramolecular-switching phenomenon have been studied by detail spectroscopic and microscopic experiments in a gel as well as in the solution state and are well supported by DFT calculations.     

Anion–π Slides for Transmembrane Transport

The recognition and transport of anions is usually accomplished by hydrogen bonding, ion pairing, metal coordination, and anion–dipole interactions. Here, we elaborate on the concept to use anion–π interactions for this purpose. Different to the popular cation–π interactions, applications of the complementary π‐acidic surfaces do not exist. This is understandable because the inversion of the aromatic quadrupole moment to produce π‐acidity is a rare phenomenon. Here, we suggest that π‐acidic aromatics can be linked together to produce an unbendable scaffold with multiple binding sites for anions to move along across a lipid bilayer membrane. The alignment of multiple anion–π sites is needed to introduce a cooperative multi‐ion hopping mechanism. Experimental support for the validity of the concept comes from preliminary results with oligonaphthalenediimide (O‐NDI) rods. Predicted by strongly positive facial quadrupole moments, the cooperativity and chloride selectivity found for anion transport by O‐NDI rods were consistent with the existence of anion–π slides. The proposed mechanism for anion transport is supported by DFT results for model systems, as well as MD simulations of rigid O‐NDI rods. Applicability of anion–π slides to achieve electroneutral photosynthesis is elaborated with the readily colorizable oligoperylenediimide (O‐PDI) rods. To clarify validity, scope and limitations of these concepts, a collaborative research effort will be needed to address by computer modeling and experimental observations the basic questions in simple model systems and to design advanced multifunctional anion–π architectures.     

Display Selection of a Hybrid Foldamer–Peptide Macrocycle

Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential to bind biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A foldamer was first identified that undergoes flexizyme-mediated tRNA acylation and that is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer–peptide hybrids. A hybrid macrocyclic nanomolar binder to the C-lobe of the E6AP HECT domain was selected that showed a highly converged peptide sequence. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions with the target protein. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. These results altogether represent a significant extension of the chemical space amenable to display selection and highlight possible benefits of inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition.     

Dynamic Vapochromic Behaviors of Organic Crystals Based on the Open–Close Motions of S‐Shaped Donor–Acceptor Folding Units

The first vapochromic organic crystals are described with respect to their preparation, color change, adsorption/desorption properties, crystal structures, and color‐change mechanism. Non‐solvatochromic, 1,4,5,8‐naphthalene‐tetracarboxylic diimide (NDI) derivatives 1 a bearing two pyrrole imine (PI) tethers have been used as a motif for the crystal packing template. Red‐purple vapochromic solid 3 was prepared by evacuation of orange crystals 2 (equivalent to 1 a ?2 MeOH), obtained by recrystallization of 1 a from MeOH. Solid 3 showed high‐adsorption ability and unprecedented vapor‐dependent color changes upon exposure to a variety of organic vapors, whereas light brown amorphous solid 1 a , did not show vapo‐ or solvatochromic behavior toward any organic solvent. The strong adsorption capability of 3 was confirmed by TGA experiments and adsorption/desorption isotherms. Analysis of the solid‐state UV/Vis analysis revealed that the vapor‐dependent color changes of 3 were owed to the specific interference of solvent vapors with its broad CT absorbance at λ=450–650 nm. Packing structures of 1 a in orange crystals 2 , red‐purple solid 3 , and regenerated orange solid 2 were unequivocally established by single crystal and synchrotron powder X‐ray diffraction, respectively. Molecular structures and arrays of 1 a in these materials indicated that 1) unit 1 a had an S‐shaped folded conformation in 2 and 3 by intramolecular donor–acceptor interactions between NDI and two PI units; 2) inclusion of the guest vapor into the S‐shaped template decreased the intramolecular PI‐NDI interactions, accompanied by increasing intermolecular NDI‐NDI and PI‐PI interactions; and 3) such flexible, open–close motions of the S‐shaped template could be repeated during reversible adsorption/desorption processes without degradation of crystal packing. The adsorption properties and mechanism of molecular shape‐dependent vapochromic behavior of 3 are discussed with reference to experimental results, crystallographic data, and theoretical calculations.     

Novel network morphology of poly(p‐oxybenzoyl)

Polymerization of 4‐acetoxybenzoic acid (ABA) with 3,5‐diacetoxybenzoic acid (DABA) was examined to control the morphology of poly(p‐oxybenzoyl) (POB). Polymerizations were carried out at a concentration of 1.0% in an aromatic solvent Therm S‐1000® (mixture of dibenzyltoluene) at 320 °C. Polymerization of ABA yielded the POB fibrillar crystals, but the polymerization with DABA at a concentration in the feed (χ_f) of 0.10–0.15 afforded novel network structures comprised of spheres connected by fibrillar crystals. The diameter of the spheres prepared at χ_f of 0.15, which were 0.7 and 5.0 μm, showed bimodality. The network distance, fibril length, and fibril width were 6.1, 2.6, and 0.1 μm, respectively. They possessed high crystallinity. The network structure was formed as follows. Co‐oligomers were first precipitated in the beginning of the polymerization by liquid–liquid phase separation to form the microdroplets. The fibrillar crystals were formed in the coalesced spheres by the crystallization of oligomers induced by the increase of molecular weight. The fibrillar crystals connecting the spheres gradually appeared owing to the shrinkage of the spheres. The fibrillar crystals grew from the surface of the spheres with the crystallization of homo‐oligomers of 4‐oxybenzoyl units, and finally the network structure was completed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 1624–1634, 2005     

Stimuli‐Responsive Self‐Assembly of a Naphthalene Diimide by Orthogonal Hydrogen Bonding and Its Coassembly with a Pyrene Derivative by a Pseudo‐Intramolecular Charge‐Transfer Interaction

A naphthalene diimide (NDI) building block containing hydrazide (H1) and hydroxy (H2) groups self‐assembled into a reverse‐vesicular structure in methylcyclohexane by orthogonal H‐bonding and π‐stacking. At an elevated temperature (LCST=43 °C), destruction of the assembled structure owing to selective dissociation of H2–H2 H bonding led to macroscopic precipitation. Further heating resulted in homogeneous redispersion of the sample at 70 °C (UCST) and the formation of a reverse‐micellar structure. In the presence of a pyridine (H3)‐functionalized pyrene (PY) donor, a supramolecular dyad (NDI–PY) was formed by H2–H3 H‐bonding. Slow transformation into an alternate NDI–PY stack occurred by a folding process due to the charge‐transfer interaction between NDI and PY. The mixed NDI–PY assembly exhibited a morphology transition from a reverse micelle (with a NDI–PY mixed‐stack core) below the LCST to another reverse micelle (with a NDI core) above the UCST via a “denatured” intermediate.     

Hydrogen-bonding-mediated vesicular assembly of functionalized naphthalene-diimide-based bolaamphiphile and guest-induced gelation in water

This paper describes the spontaneous vesicular assembly of a naphthalene-diimide (NDI)-based non-ionic bolaamphiphile in aqueous medium by using the synergistic effects of π-stacking and hydrogen bonding. Site isolation of the hydrogen-bonding functionality (hydrazide), a strategy that has been adopted so elegantly in nature, has been executed in this system to protect these moieties from the bulk water so that the distinct role of hydrogen bonding in the self-assembly of hydrazide-functionalized NDI building blocks could be realized, even in aqueous solution. Furthermore, the electron-deficient NDI-based bolaamphiphile could engage in donor-acceptor (D-A) charge-transfer (CT) interactions with a water-insoluble electron-rich pyrene donor by virtue of intercalation of the latter chromophore in between two NDI building blocks. Remarkably, even when pyrene was located between two NDI blocks, intermolecular hydrogen-bonding networks between the NDI-linked hydrazide groups could be retained. However, time-dependent AFM studies revealed that the radius of curvature of the alternately stacked D-A assembly increased significantly, thereby leading to intervesicular fusion, which eventually resulted in rupturing of the membrane to form 1D fibers. Such 2D-to-1D morphological transition produced CT-mediated hydrogels at relatively higher concentrations. Instead of pyrene, when a water-soluble carboxylate-functionalized pyrene derivative was used as the intercalator, non-covalent tunable in-situ surface-functionalization could be achieved, as evidenced by the zeta-potential measurements.     

Designing Foldamer–Foldamer Interactions in Solution: The Roles of Helix Length and Terminus Functionality in Promoting the Self‐Association of Aminoisobutyric Acid Oligomers

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure–activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen‐bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D₆]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X‐ray crystallography studies of two oligomers allowed a comparison of the inter‐ and intramolecular hydrogen‐bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer–foldamer interactions. These solution‐based and solid‐state studies indicated that the preferred geometry for aggregation is through head‐to‐tail interactions between the N and C termini of adjacent Aib oligomers.     

Donor–Acceptor Heterojunction Configurations Based on DNA–Multichromophore Arrays

Multichromophore arrays of bis(2‐thienyl)diketopyrrolopyrrole (DPP) and naphthalenediimide (NDI) with two Zn^II‐cyclens were constructed using thymidine DNA as a scaffold through the binding of the Zn^II‐cyclens with thymine bases. We demonstrate photocurrent generation in a donor–acceptor heterojunction configuration consisting of the DPP (donor) and NDI (acceptor) arrays co‐immobilized on an Au electrode. The co‐immobilized electrode exhibited good photocurrent responses because of the efficient charge separation between the DPP and NDI arrays. In contrast, an immobilized electrode consisting of randomly assembled DPP‐NDI arrays generated no photocurrent response because DPP formed ground‐state charge‐transfer complexes with NDI in the randomly assembled arrays. Therefore, our approach to generate donor–acceptor heterojunctions based on DNA–multichromophore arrays is a useful method to efficiently generate photocurrent.     

Aromatically functionalized cyclic tricholate macrocycles: aggregation, transmembrane pore formation, flexibility, and cooperativity

The aggregation of macrocyclic oligocholates with introverted hydrophilic groups and aromatic side chains was studied by fluorescence spectroscopy and liposome leakage assays. Comparison between the solution and the membrane phase afforded insight into the solvophobically driven aggregation. The macrocycles stacked over one another in lipid membranes to form transmembrane nanopores, driven by a strong tendency of the water molecules in the interior of the amphiphilic macrocycles to aggregate in a nonpolar environment. The aromatic side chains provided spectroscopic signatures for stacking, as well as additional driving force for the aggregation. Smaller, more rigid macrocycles stacked better than larger, more flexible ones because the cholate building blocks in the latter could rotate outward and diminish the conformation needed for the water-templated hydrophobic stacking. The acceptor-acceptor interactions among naphthalenediimide (NDI) groups were more effective than the pyrene-NDI donor-acceptor interactions in promoting the transmembrane pore formation of the oligocholate macrocycles.