Magnifying the Structural Components of Biomembranes: A Prototype for the Study of the Self‐Assembly of Giant Lipids

How biomembranes are self‐organized to perform their functions remains a pivotal issue in biological and chemical science. Understanding the self‐assembly principles of lipid‐like molecules hence becomes crucial. Herein, we report the mesostructural evolution of amphiphilic sphere‐rod conjugates (giant lipids), and study the roles of geometric parameters (head–tail ratio and cross‐sectional area) during this course. As a prototype system, giant lipids resemble natural lipidic molecules by capturing their essential features. The self‐assembly behavior of two categories of giant lipids (I‐shape and T‐shape, a total of 8 molecules) is demonstrated. A rich variety of mesostructures is constructed in solution state and their molecular packing models are rationally understood. Giant lipids recast the phase behavior of natural lipids to a certain degree and the abundant self‐assembled morphologies reveal distinct physiochemical behaviors when geometric parameters deviate from natural analogues.     

Spontaneous formation of narrowly‐distributed self‐assembly from polyamidoamine dendron‐poly(L‐lysine) block copolymers through helix‐coil transition of poly(L‐lysine) block

The self‐assembly of head‐tail type block copolymers composed of polyamidoamine dendron head block and poly(L ‐lysine) (PLL) tail block was studied using a light scattering technique and transmission electron microscopy. A PLL tail block in a head‐tail type block copolymer exhibits a coil‐to‐helix transition as a result of the change in solvent quality from water to methanol. When the PLL tail block takes a helical conformation in high methanol content, the resulting head‐tail type block copolymer has a defined three‐dimensional structure like that of a protein molecule. Self‐assemblies of such block copolymers having a totally fixed molecular shape spontaneously form polymersome‐like self‐assemblies with an extremely narrow size distribution through converging to a thermodynamically stable assembling state. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1217–1223, 2009     

Giant surfactants based on molecular nanoparticles: Precise synthesis and solution self‐assembly

Giant surfactants are polymer‐tethered molecular nanoparticles (MNPs) and can be considered as a subclass of giant molecules. The MNPs serve as functionalized heads with persistent shape and volume, which may vary in size, symmetry, and surface chemistry. The covalent conjugation of MNPs and polymer tails affords giant surfactants with diverse composition and architecture. Synthetic strategies such as “grafting‐from” and “grafting‐onto” have been successfully applied to the precise synthesis of giant surfactants, which is further facilitated by the emergence of “click” chemistry reactions. In many aspects, giant surfactants capture the essential features of small‐molecule surfactants, yet they have much larger sizes. They bridge the gap between small‐molecule surfactants and traditional amphiphilic macromolecules. Their self‐assembly behaviors in solution are summarized in this Review. Micelle formation is affected not only by their primary chemical structures, but also by the experimental conditions. This new class of materials is expected to deliver general implications on the design of novel functional materials based on MNP building blocks in the bottom‐up fabrication of well‐defined nanostructures. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014 , 52, 1309–1325     

Magneto‐Adaptive Surfactants Showing Anti‐Curie Behavior and Tunable Surface Tension as Porogens for Mesoporous Particles with 12‐Fold Symmetry

Gaining external control over self‐organization is of vital importance for future smart materials. Surfactants are extremely valuable for the synthesis of diverse nanomaterials. Their self‐assembly is dictated by microphase separation, the hydrophobic effect, and head‐group repulsion. It is desirable to supplement surfactants with an added mode of long‐range and directional interaction. Magnetic forces are ideal, as they are not shielded in water. We report on surfactants with heads containing tightly bound transition‐metal centers. The magnetic moment of the head was varied systematically while keeping shape and charge constant. Changes in the magnetic moment of the head led to notable differences in surface tension, aggregate size, and contact angle, which could also be altered by an external magnetic field. The most astonishing result was that the use of magnetic surfactants as structure‐directing agents enabled the formation of porous solids with 12‐fold rotational symmetry.     

Self‐Assembly of Ambidentate Pyridyl‐Carboxylate Ligands with Octahedral Ruthenium Metal Centers: Self‐Selection for a Single‐Linkage Isomer and Anticancer‐Potency Studies

The synthesis of six new [2+2] metallarectangles through the coordination‐driven self‐assembly of octahedral Ru^II‐based acceptors with ambidentate pyridyl‐carboxylate donors is described. These molecular rectangles are fully characterized by ¹H NMR spectroscopy, high‐resolution electrospray mass spectrometry, and single‐crystal X‐ray diffraction. In each case, despite the possible formation of multiple isomers, based on the relative orientation of the pyridyl and carboxylate groups (head‐to‐head versus head‐to‐tail), evidence for the formation of a single preferred ensemble (head‐to‐tail) was found in the ¹H NMR spectra. Furthermore, the cytotoxicities of all of the rectangles were established against A549 (lung), AGS (gastric), HCT‐15 (colon), and SK hep 1 (liver) human cancer cell lines. The cytotoxicities of rectangles that contained the 5,8‐dihydroxy‐1,4‐naphthaquinonato bridging moiety between the Ru centers ( 9 – 11 ) were particularly high against AGS cancer cells, with IC₅₀ values that were comparable to that of reference drug cisplatin.     

Dissymmetrical U‐Shaped π‐Stacked Supramolecular Assemblies by Using a Dinuclear CuI Clip with Organophosphorus Ligands and Monotopic Fully π‐Conjugated Ligands

Reactions between the U‐shaped binuclear Cu^I complex A that bears short metal–metal distances and the cyano‐capped monotopic π‐conjugated ligands 1 – 5 that carry gradually bulkier polyaromatic terminal fragments lead to the formation of π‐stacked supramolecular assemblies 6 – 10 , respectively, in yields of 50–80 %. These derivatives have been characterized by multinuclear NMR spectroscopic analysis and X‐ray diffraction studies. Their solid‐state structures show the selective formation of U‐shaped supramolecular assemblies in which two monotopic π‐conjugated systems present large ( 6 , 7 , and 9 ) or medium ( 8 and 10 ) intramolecular π overlap, thus revealing π–π interactions. These assemblies self‐organize into head‐to‐tail π‐stacked dimers that in turn self‐assemble to afford infinite columnar π stacks. The nature, extent, and complexity of the intermolecular contacts within the head‐to‐tail π‐stacked dimer depend on the nature of the terminal polyaromatic fragment carried by the cyano‐capped monotopic ligand, but it does not alter the result of the self‐assembling process. These results demonstrate that the dinuclear molecular clip A that bears short metal–metal distances allows selective supramolecular assembly processes driven by the formation of intra‐ and intermolecular short π–π interactions in the resulting self‐assembled structures; thus, demonstrating that their shape is not only dictated by the symmetry of the building blocks. This approach opens perspectives toward the formation of extended π‐stacked columns based on dissymmetrical and functional π‐conjugated systems.     

Self‐Assembly of Bolaamphiphilic Molecules

The current buzzword in science and technology is self‐assembly and molecular self‐assembly is one of the most prominent fields as far as research in chemical and biological sciences is concerned. Generally, self‐assembly of molecules occurs through weak non‐covalent interactions like hydrogen bonding, π–π stacking, hydrophobic effects, etc. Inspired by many natural systems consisting of self‐assembled structures, scientists have been trying to understand their formation and mimic such processes in the laboratory to create functional “smart” materials, which respond to temperature, light, pH, electromagnetic field, mechanical stress, and/or chemical stimuli. These responses are usually manifested as remarkable changes from the molecular (e. g., conformational state, hierarchical order) to the macroscopic level (e. g., shape, surface properties). Many molecules such as peptides, viruses, and surfactants are known to self‐assemble into different structures. Among them, glycolipids are the new entries in the area of molecules that are being investigated for their self‐assembly characteristics. Among the different classes of glycolipids like rhamnolipids and trehalose lipids, owing to their biological preparations and their structural novelty, sophorolipids (SLs) are evoking greater interest among researchers. Sophorolipids are a class of asymmetric bolas bearing COOH groups at one end and sophorose (dimeric glucose linked by an unusual β(1→2) linkage). The extreme membrane stability of Archaea, attributed to the membrane‐spanning bolas (tetraether glycolipids), has inspired chemists to unravel the molecular designs that underpin the self‐assembly of bolaamphiphilic molecules. Apart from these self‐assembled structures, bolaamphiphiles find applications in many fields such as drug delivery, membrane mimicking, siRNA therapies, etc. The first part of this Personal Account presents some possible self‐assembled structures of bolaamphiphiles and their mechanism of formation. The later part covers our work on one of the typical bolaamphiphiles known as sophorolipids.     

Effect of Head‐Group Chemistry on Surface‐Mediated Molecular Self‐Assembly

Surface molecular self‐assembly is a fast advancing field with broad applications in sensing, patterning, device assembly, and biochemical applications. A vast number of practical systems utilize alkane thiols supported on gold surfaces. Whereas a strong Au? S bond facilitates robust self‐assembly, the interaction is so strong that the surface is reconstructed, leaving etch pits that render the monolayers susceptible to degradation. By using different head group elements to adcust the molecule–surface interaction, a vast array of new systems with novel properties may be formed. In this paper we use a carefully chosen set of molecules to make a direct comparison of the self‐assembly of thioether, selenoether, and phosphine species on Au(111). Using the herringbone reconstruction of gold as a sensitive readout of molecule–surface interaction strength, we correlate head‐group chemistry with monolayer (ML) properties. It is demonstrated that the hard/soft rules of inorganic chemistry can be used to rationalize the observed trend of molecular interaction strengths with the soft gold surface, that is, P>Se>S. We find that the structure of the monolayers can be explained by the geometry of the molecules in terms of dipolar, quadrupolar, or van der Waals interactions between neighboring species driving the assembly of distinct ordered arrays. As this study directly compares one element with another in simple systems, it may serve as a guide for the design of self‐assembled monolayers with novel structures and properties.     

Strain‐Promoted Thiol‐Mediated Cellular Uptake of Giant Substrates: Liposomes and Polymersomes

Simple cyclic disulfides under high tension mediate the uptake of giant substrates, that is, liposomes and polymersomes with diameters of up to 400 nm, into HeLa Kyoto cells. To place them at the surface of the vesicles, the strained disulfides were attached to the head‐group of cationic amphiphiles. Bell‐shaped dose response curves revealed self‐activation of the strained amphiphiles by self‐assembly into microdomains at low concentrations and self‐inhibition by micelle formation at high concentrations. Poor colocalization of internalized vesicles with endosomes, lysosomes, and mitochondria indicate substantial release into the cytosol. The increasing activity with disulfide ring tension, inhibition with Ellman's reagent, and inactivity of maleimide and guanidinium controls outline a distinct mode of action that deserves further investigation and is promising for practical applications.     

The Origin of Hierarchical Structure Formation in Highly Grafted Symmetric Supramolecular Double‐Comb Diblock Copolymers

Involving supramolecular chemistry in self‐assembling block copolymer systems enables design of complex macromolecular architectures that, in turn, could lead to complex phase behavior. It is an elegant route, as complicated and sensitive synthesis techniques can be avoided. Highly grafted double‐comb diblock copolymers based on symmetric double hydrogen bond accepting poly(4‐vinylpyridine)‐block‐poly(N‐acryloylpiperidine) diblock copolymers and donating 3‐nonadecylphenol amphiphiles are realized and studied systematically by changing the molecular weight of the copolymer. Double perpendicular lamellae‐in‐lamellae are formed in all complexes, independent of the copolymer molecular weight. Temperature‐resolved measurements demonstrate that the supramolecular nature and ability to crystallize are responsible for the formation of such multiblock‐like structures. Because of these driving forces and severe plasticization of the complexes in the liquid crystalline state, this supramolecular approach can be useful for steering self‐assembly of both low‐ and high‐molecular‐weight block copolymer systems.     

Classical Amphiphilic Behavior of Nonclassical Amphiphiles: A Comparison of Metallacarborane Self‐Assembly with SDS Micellization

The self‐assembly of metallacarboranes, a peculiar family of compounds exhibiting surface activity and resembling molecular‐scale Pickering stabilizers, has been investigated by comparison to the micellization of sodium dodecylsulfate (SDS). These studies have shown that molecules without classical amphiphilic topology but with an inherent amphiphilic nature can behave similarly to classical surfactants. As shown by NMR techniques, the self‐assembly of both metallacarboranes and SDS obey a closed association model. However, the aggregation of metallacarboranes is found to be enthalpy‐driven, which is very unusual for classical surfactants. Possible explanations of this fact are outlined.     

Water‐Rich Fluid Material Containing Orderly Condensed Proteins

A fluid material with high protein content (120–310 mg mL⁻¹) was formed through the ordered self‐assembly of native proteins segregated from water. This material is instantly prepared by the simple mixing of a protein solution with anionic and cationic surfactants. By changing the ratio of the surfactants based on the electrostatic characteristics of the target protein, we observed that the surfactants could function as a versatile molecular glue for protein assembly. Moreover, these protein assemblies could be disassembled back into an aqueous solution depending on the salt conditions. Owing to the water‐retaining properties of the hydrophilic part of surfactants, the proteins in this material are in a water‐rich environment, which maintains their native structure and function. The inclusion of water also provides functional extensibility to this material, as demonstrated by the preparation of an enzymatically active gel. We anticipate that the unique features of this material will permit the use of proteins not only in solution but also as elements of integrated functionalized materials.     

Self‐Assembly of Giant Spherical Liquid‐Crystalline Complexes and Formation of Nanostructured Dynamic Gels that Exhibit Self‐Healing Properties

Supramolecular self‐assembly of 24 forklike mesogenic ligands and 12 transition metal ions led to the formation of giant spherical coordination complexes that exhibit liquid‐crystalline (LC) phases. Self‐healing LC supramolecular gels were also obtained through the introduction of these LC nanostructured supramolecular giant spherical complexes into dynamic covalent networks formed by cross‐linkers and bifunctional polymers. The giant spherical structures of the Pd^II complexes with 72 rodlike moieties on the periphery were characterized by NMR, diffusion‐ordered NMR spectroscopy, and mass spectrometry. These complexes are stable and exhibit lyotropic LC behavior, while the mesogenic ligands show thermotropic LC properties. The self‐assembled LC structures of the spherical complexes can be tuned by the length of the rodlike moieties.     

The Helix to Super‐Helix Transition in the Self‐Assembly of π‐Systems: Superseding of Molecular Chirality at Hierarchical Level

Higher‐order super‐helical structures derived from biological molecules are known to evolve through opposite coiling of the initial helical fibers, as seen in collagen protein. A similar phenomenon is observed in a π‐system self‐assembly of chiral oligo(phenyleneethylene) derivatives (S )‐ 1 and (R )‐ 1 that explains the unequal formation of both left‐ and right‐handed helices from molecule having a specific chiral center. Concentration‐ and temperature‐dependent circular dichroism (CD) and UV/Vis spectroscopic studies revealed that the initial formation of helical aggregates is in accordance with the molecular chirality. At the next level of hierarchical self‐assembly, coiling of the fibers occurs with opposite handedness, thereby superseding the command of the molecular chirality. This was confirmed by solvent‐dependent decoiling of super‐helical structures and concentration‐dependent morphological analysis.     

Reversible pH‐ and Photocontrollable Carbohydrate‐Based Surfactants

The parallel synthesis and properties of a library of photoswitchable surfactants comprising a hydrophobic butylazobenzene tail‐group and a hydrophilic carbohydrate head‐group, including the first surfactants to exhibit dual photo‐ and pH‐responsive behavior, is reported. This new generation of surfactants shows varying micelle morphologies, photocontrollable surface tension, and pH‐induced aggregation and adsorption.     

Reciprocal Self‐Assembly of Peptide–DNA Conjugates into a Programmable Sub‐10‐nm Supramolecular Deoxyribonucleoprotein

To overcome the limitations of molecular assemblies, the development of novel supramolecular building blocks and self‐assembly modes is essential to create more sophisticated, complex, and controllable aggregates. The self‐assembly of peptide–DNA conjugates (PDCs), in which two orthogonal self‐assembly modes, that is, β‐sheet formation and Watson–Crick base pairing, are covalently combined in one supramolecular system, is reported. Despite extensive research, most self‐assembly studies have focused on using only one type of building block, which restricts structural and functional diversity compared to multicomponent systems. Multicomponent systems, however, suffer from poor control of self‐assembly behaviors. Covalently conjugated PDC building blocks are shown to assemble into well‐defined and controllable nanostructures. This controllability likely results from the decrease in entropy associated with the restriction of the molecular degrees of freedom by the covalent constraints. Using this strategy, the possibility to thermodynamically program nano‐assemblies to exert gene regulation activity with low cytotoxicity is demonstrated.     

Sequence‐Mandated,Distinct Assembly of Giant Molecules

Although controlling the primary structure of synthetic polymers is itself a great challenge, the potential of sequence control for tailoring hierarchical structures remains to be exploited, especially in the creation of new and unconventional phases. A series of model amphiphilic chain‐like giant molecules was designed and synthesized by interconnecting both hydrophobic and hydrophilic molecular nanoparticles in precisely defined sequence and composition to investigate their sequence‐dependent phase structures. Not only compositional variation changed the self‐assembled supramolecular phases, but also specific sequences induce unconventional phase formation, including Frank–Kasper phases. The formation mechanism was attributed to the conformational change driven by the collective hydrogen bonding and the sequence‐mandated topology of the molecules. These results show that sequence control in synthetic polymers can have a dramatic impact on polymer properties and self‐assembly.     

Sequence‐Mandated,Distinct Assembly of Giant Molecules

Although controlling the primary structure of synthetic polymers is itself a great challenge, the potential of sequence control for tailoring hierarchical structures remains to be exploited, especially in the creation of new and unconventional phases. A series of model amphiphilic chain‐like giant molecules was designed and synthesized by interconnecting both hydrophobic and hydrophilic molecular nanoparticles in precisely defined sequence and composition to investigate their sequence‐dependent phase structures. Not only compositional variation changed the self‐assembled supramolecular phases, but also specific sequences induce unconventional phase formation, including Frank–Kasper phases. The formation mechanism was attributed to the conformational change driven by the collective hydrogen bonding and the sequence‐mandated topology of the molecules. These results show that sequence control in synthetic polymers can have a dramatic impact on polymer properties and self‐assembly.     

Dramatic Specific‐Ion Effect in Supramolecular Hydrogels

We report on a pronounced specific‐ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular weight peptide‐based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel‐phase materials were formed due to molecular self‐assembly, driven by a combination of hydrogen bonding and π‐stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc‐YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G′ values between 0.8 kPa and 2.4 kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self‐assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H‐bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self‐assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc‐VL and Fmoc‐LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc‐AA. To get more insights into the molecular mechanism, the effect of anions on sol–gel equilibrium was investigated, which indicates the observed changes result from the specific‐ion effects on gels structure, rather than on the sol–gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self‐assembly.     

“Raft” Formation by Two‐Dimensional Self‐Assembly of Block Copolymer Rod Micelles in Aqueous Solution

Block copolymers can form a broad range of self‐assembled aggregates. In solution, planar assemblies usually form closed structures such as vesicles; thus, free‐standing sheet formation can be challenging. While most polymer single crystals are planar, their growth usually occurs by uptake of individual chains. Here we report a novel lamella formation mechanism: core‐crystalline spherical micelles link up to form rods in solution, which then associate to yield planar arrays. For the system of poly(ethylene oxide)‐block‐polycaprolactone in water, co‐assembly with homopolycaprolactone can induce a series of morphological changes that yield either rods or lamellae. The underlying lamella formation mechanism was elucidated by electron microscopy, while light scattering was used to probe the kinetics. The hierarchical growth of lamellae from one‐dimensional rod subunits, which had been formed from spherical assemblies, is novel and controllable in terms of product size and aspect ratio.