Self-assembled multivalency: dynamic ligand arrays for high-affinity binding

Multivalency is a powerful strategy for achieving high-affinity molecular recognition in biological systems. Recently, attention has begun to focus on using self-assembly rather than covalent scaffold synthesis to organize multiple ligands. This approach has a number of advantages, including ease of synthesis/assembly, tunability of nanostructure morphology and ligands, potential to incorporate multiple active units, and the responsive nature of self-assembly. We suggest that self-assembled multivalency is a strategy of fundamental importance in the design of synthetic nanosystems to intervene in biological pathways and has potential applications in nanomedicine.     

Molecular Logic Circuits

Miniaturization has been an essential ingredient in the outstanding progress of information technology over the past fifty years. The next, perhaps ultimate, limit of miniaturization is that of molecules, which are the smallest entities with definite size, shape, and properties. Recently, great effort has been devoted to design and investigate molecular‐level systems that are capable of transferring, processing, and storing information in binary form. Some of these nanoscale devices can, in fact, perform logic operations of remarkable complexity. This research—although far from being transferred into technology—is attracting interest, as the nanometer realm seems to be out of reach for the “top‐down” techniques currently available to microelectronics industry. Moreover, such studies introduce new concepts in the “old” field of chemistry and stimulate the ingenuity of researchers engaged in the “bottom‐up” approach to nanotechnology.     

What Will Chemistry Do in the Next Twenty Years?

The path of chemistry in the future will be determined both by its participation in solving large-scale societal problems and by its generation of new ideas through basic research. This article sketches four of the areas of societal “pull” in which chemistry will play a role in solving applied problems—national security, health care, the environment, and energy—and four areas in which basic research will be especially fruitful—materials chemistry, biological chemistry, computational chemistry, and chemistry exploring the limits of size and speed in chemical phenomena.     

Properties and applications of precision oligomer materials; where organic and polymer chemistry join forces

Precise oligomeric materials constitute a growing area of research with implications for various applications as well as fundamental studies. Notably, this field of science which can be termed macro-organic chemistry, draws inspiration from both traditional polymer chemistry and organic synthesis, combining the molecular precision of organic chemistry with the materials properties of macromolecules. Discrete oligomers enable access to unprecedented materials properties, for example, in self-assembled structures, crystallization, or optical properties. The degree of control over oligomer structures resembles many biological systems and enables the design of materials with tailored properties and the development of fundamental structure–property relationships. This Review highlights recent developments in macro-organic chemistry from synthetic concepts to materials properties, with a focus on self-assembly and molecular recognition. Finally, an outlook for future research directions is provided.     

Selective Host Molecules Obtained by Dynamic Adaptive Chemistry

Up till 20 years ago, in order to endow molecules with function there were two mainstream lines of thought. One was to rationally design the positioning of chemical functionalities within candidate molecules, followed by an iterative synthesis–optimization process. The second was the use of a “brutal force” approach of combinatorial chemistry coupled with advanced screening for function. Although both methods provided important results, “rational design” often resulted in time‐consuming efforts of modeling and synthesis only to find that the candidate molecule was not performing the designed job. “Combinatorial chemistry” suffered from a fundamental limitation related to the focusing of the libraries employed, often using lead compounds that limit its scope. Dynamic constitutional chemistry has developed as a combination of the two approaches above. Through the rational use of reversible chemical bonds together with a large plethora of precursor libraries, one is now able to build functional structures, ranging from quite simple molecules up to large polymeric structures. Thus, by introduction of the dynamic component within the molecular recognition processes, a new perspective of deciphering the world of the molecular events has aroused together with a new field of chemistry. Since its birth dynamic constitutional chemistry has continuously gained attention, in particular due to its ability to easily create from scratch outstanding molecular structures as well as the addition of adaptive features. The fundamental concepts defining the dynamic constitutional chemistry have been continuously extended to currently place it at the intersection between the supramolecular chemistry and newly defined adaptive chemistry, a pivotal feature towards evolutive chemistry.     

Supramolecular Inorganic Chemistry: Small Guests in Small and Large Hosts

A key reaction in the biological and material world is the controlled linking of simple (molecular) building blocks, a reaction with which one can create mesoscopic structures, which, for example, contain cavities and display specifically desired properties, but also compounds that exhibit typical solid-state structures. The best example in this context is the chemistry of host–guest interactions, which spans the entire range from three- and two-dimensional to one- and “zero-dimensional”, discrete host structures. Members of the class of multidimensional compounds have been classified as such for a long time, for example, clathrates and intercalation compounds. Thus far, however, there are no classifications for discrete inorganic host–guest compounds. The first systematic approach can be applied to novel polyoxometalates, a class of compounds which has only recently become known. Molecular recognition; tailor-made, molecular engineering; control of fragment linkage of spin organization and crystallization; cryptands and coronands as “cages” for cations, anions or anion–cation aggregates as sections of ionic lattices; anions within anions, receptors; host–guest interactions; complementarity, as well as the dialectic terms reduction and emergence are important terms and concepts of supramolecular inorganic chemistry. Of particular importance for future research is the comprehension of the mesoscopic area (molècular assemblies)—that between individual molecules and solids (“substances”)—which acts in the biological world as carrier of function and information and for which interesting material properties are expected. This area is accessible through certain variations of “controlled” self-organization processes, which can be demonstrated by using examples from the chemistry of polyoxometalates. The comprehension of the laws that rule the linking of simple polyhedra to give complex systems enables one to deal with numerous interdisciplinary areas of research: crystal physics and chemistry, heterogeneous catalysis, bioinorganic chemistry (biomineralization), and materials science. In addition, conservative self-organization processes, for example template-directed syntheses, are of importance for natural philosophy in the context of the question about the inherent properties of material systems.     

“Second Organized Structures” of Nanoscale Inorganic Polyoxomolybdate Compounds

Growth of polyoxomolybdate (POM) clusters and the main role of pentagonal {(Mo)Mo₅}-type building blocks in the construction principle for nanoscale inorganic polyoxomolybdate compounds were introduced. The peculiar self-assembly of the nanoscale inorganic ions in aqueous solutions was reviewed. The concepts of “second organized structures” of nanoscale inorganic molybdenum compounds and the mixtures of POMs/surfactants were proposed.     

Towards polyoxometalate-integrated nanosystems

Polyoxometalates represent a diverse range of molecular clusters with an almost unmatched range of physical properties and the ability to form structures that can bridge several length scales. The new building block principles that have been discovered are beginning to allow the design of complex clusters with desired properties and structures; several structural types and novel physical properties are examined herein. The overall message that is presented throughout is the possibility that polyoxometalate clusters could be excellent candidates to be exploited in the development of functional nanosystems or nanodevices. The concepts that underpin the development of nanoscale devices are discussed briefly, as are the considerable challenges that must be overcome to realise polyoxometalate-based functional nanosystems.     

A Periodic System of Supramolecular Elements

Chemistry “beyond the molecule” is based on weak, noncovalent, and reversible interactions. As a consequence of these bonds being weak, structural organization by folding and self‐assembly can only be fully exploited with larger molecules that can provide multiple binding sites. Such “supramolecules” can now be synthesized and their folding into desired conformations predicted. A new level of chemistry can now be realized through the creation of non‐natural entities composed of molecular building blocks with defined secondary structures. Herein we define these building blocks as “supramolecular elements”. We anticipate that further research on such large molecules will reveal construction principles dictated by recurring motifs that govern structure formation through folding and self‐assembly. These principles are comparable to the organization of atoms in the Periodic Table of Chemical Elements and may lead to the establishment of a Periodic System of Supramolecular Elements.     

Ill‐defined chemical concepts: The problem of quantification

From time to time, ill‐defined concepts leads to never‐ending discussions in the chemical literature. “Is there a quadruple bond in the C₂ molecule? What about the boron–boron triple bond? Can we uniquely define concepts like aromaticity or bond order at all?” With this tutorial review I would like to point out that some of the contemporary publications in chemistry are characterized by a confusion of ideas and concepts, and in part ill definitions. And, that exactly those ill‐defined concepts lead to never ending controversies in the literature. Examples of well‐ and ill‐defined concepts in chemistry are discussed.     

High-tech applications of self-assembling supramolecular nanostructured gel-phase materials: from regenerative medicine to electronic devices

It is likely that nanofabrication will underpin many technologies in the 21st century. Synthetic chemistry is a powerful approach to generate molecular structures that are capable of assembling into functional nanoscale architectures. There has been intense interest in self-assembling low-molecular-weight gelators, which has led to a general understanding of gelation based on the self-assembly of molecular-scale building blocks in terms of non-covalent interactions and packing parameters. The gelator molecules generate hierarchical, supramolecular structures that are macroscopically expressed in gel formation. Molecular modification can therefore control nanoscale assembly, a process that ultimately endows specific material function. The combination of supramolecular chemistry, materials science, and biomedicine allows application-based materials to be developed. Regenerative medicine and tissue engineering using molecular gels as nanostructured scaffolds for the regrowth of nerve cells has been demonstrated in vivo, and the prospect of using self-assembled fibers as one-dimensional conductors in gel materials has captured much interest in the field of nanoelectronics.     

Nanoparticles as macromolecules

A review of recent trends in the dispersion, purification, and assembly of colloidal nanoparticles highlights a number of growing analogies with ideas borrowed from polymer science. Beyond the similar scales of size, several key concepts lying at the foundation of polymer physics—such as polydispersity, fractionation, phase ordering, and viscoelasticity—are taking on new and unique significance in the contemporary realm of nanotechnology. Leveraging “soft matter” at the nanoscale to simplify materials processing and improve material performance is becoming a reality, with potentially profound implications for a number of emerging technologies. © 2013 Wiley Periodicals, Inc. J Polym Sci Part B: Polym. Phys. 2013 , 51, 1195–1208     

Perspectives in Supramolecular Chemistry—From Molecular Recognition towards Molecular Information Processing and Self-Organization

The selective binding of a substrate by a molecular receptor to form a supramolecular species involves molecular recognition which rests on the molecular information stored in the interacting species. The functions of supermolecules cover recognition, as well as catalysis and transport. In combination with polymolecular organization, they open ways towards molecular and supramolecular devices for information processing and signal generation. The development of such devices requires the design of molecular components performing a given function (e.g., photoactive, electroactive, ionoactive, thermoactive, or chemoactive) and suitable for assembly into an organized array. Light-conversion devices and charge-separation centers have been realized with photoactive cryptates formed by receptors containing photosensitive groups. Eleclroactive and ionoactive devices are required for carrying information via electronic and ionic signals. Redox-active polyolefinic chains, like the “caroviologens”, represent molecular wires for electron transfer through membranes. Push-pull polyolefins possess marked nonlinear optical properties. Tubular mesophases, formed by organized stacking of suitable macro-cyclic components, as well as “chundle”-type structures, based on bundles of chains grafted onto a macrocyclic support, represent approaches to ion channels. Lipophilic macrocyclic units form Langmuir-Blodgett films that may display molecular recognition at the air-water interface. Supramolecular chemistry has relied on more or less preorganized molecular receptors for effecting molecular recognition, catalysis, and transport processes. A step beyond preorganization consists in the design of systems undergoing self-organization, that is, systems capable of spontaneously generating a well-defined supramolecular architecture by self-assembling from their components under a given set of conditions. Several approaches to self-assembling systems have been pursued: the formation of helical metal complexes, the double-stranded helicates, which result from the spontaneous organization of two linear polybipyridine ligands into a double helix by binding of specific metal ions; the generation of mesophases and liquid crystalline polymers of supramolecular nature from complementary components, amounting to macroscopic expression of molecular recognition; the molecular-recognition-directed formation of ordered solid-state structures. Endowing photo-, electro-, and ionoactive components with recognition elements opens perspectives towards the design of programmed molecular and supramolecular systems capable of self-assembly into organized and functional supramolecular devices. Such systems may be able to perform highly selective operations of recognition, reaction, transfer, and structure generation for signal and information processing at the molecular and supramolecular levels.     

Introducing tox-Profiles of Chemical Reactions

In this Essay, we present a critical analysis of two common practices in modern chemistry—that is, of using speculations about the “greenness” and “nontoxicity” of developed synthesis procedures and of a priori labelling various compounds derived from natural sources as being environmentally safe. We note that every organic molecule that contains functional groups should be biologically active. Thus, analysis of the particular greenness and the potential environmental impact of a given chemical process should account for the biological activity of all its components in a measureable (rather than empirical) way. We highlight the necessity of clarifying discussions on biological activity and toxicity and propose possible ways of introducing tox-Profiles as a reliable overview of the overall toxicity of chemical reactions.     

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so‐called ionophore class occupies an unflattering position in the lower branches, with typical labels being “non‐specific” and “toxic”. In fact, the mere possibility that a candidate molecule possesses “ionophore activity” typically prompts its removal from further studies; ionophores—from a chemical genetics perspective—are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.     

Multivalent ions and biomolecules: Attempting a comprehensive perspective

Ions are ubiquitous in nature. They play a key role for many biological processes on the molecular scale, from molecular interactions, to mechanical properties, to folding, to self-organisation and assembly, to reaction equilibria, to signalling, to energy and material transport, to recognition etc. Going beyond monovalent ions to multivalent ions, the effects of the ions are frequently not only stronger (due to the obviously higher charge), but qualitatively different. A typical example is the process of binding of multivalent ions, such as Ca²⁺, to a macromolecule and the consequences of this ion binding such as compaction, collapse, potential charge inversion and precipitation of the macromolecule. Here we review these effects and phenomena induced by multivalent ions for biological (macro)molecules, from the “atomistic/molecular” local picture of (potentially specific) interactions to the more global picture of phase behaviour including, e. g., crystallisation, phase separation, oligomerisation etc. Rather than attempting an encyclopedic list of systems, we rather aim for an embracing discussion using typical case studies. We try to cover predominantly three main classes: proteins, nucleic acids, and amphiphilic molecules including interface effects. We do not cover in detail, but make some comparisons to, ion channels, colloidal systems, and synthetic polymers. While there are obvious differences in the behaviour of, and the relevance of multivalent ions for, the three main classes of systems, we also point out analogies. Our attempt of a comprehensive discussion is guided by the idea that there are not only important differences and specific phenomena with regard to the effects of multivalent ions on the main systems, but also important similarities. We hope to bridge physico-chemical mechanisms, concepts of soft matter, and biological observations and connect the different communities further.     

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     

Electrospray Mass Spectrometry of Biomacromolecular Complexes with Noncovalent Interactions—New Analytical Perspectives for Supramolecular Chemistry and Molecular Recognition Processes

The development of “soft” ionization methods in recent years has enabled substantial progress in the mass spectrometric characterization of macromolecules, in particular important biopolymers such as proteins and nucleic acids. In contrast to the still existing limitations for the determination of molecular weights by other ionization methods such as fast atom bombardment and plasma desorption, electrospray ionization (ESI) and matrix-assisted laser desorption have provided a breakthrough to macromolecules larger than 100 kDa. Whereas these methods have been successfully applied to determine the molecular weight and primary structure of biopolymers, the recently discovered direct characterization by ESI-MS of complexes containing noncovalent interactions (“noncovalent complexes”) opens new perspectives for supramolecular chemistry and analytical biochemistry. Unlike other ionization methods ESI-MS can be performed in homogeneous solution and under nearly physiological conditions of pH, concentration, and temperature. ESI mass spectra of biopolymers, particularly proteins, exhibit series of multiply charged macromolecular ions with charge states and distributions (“charge structures”) characteristic of structural states in solution, which enable a differentiation between native and denatured tertiary structures. In the first part of this article, fundamental principles, the present knowledge about ion formation mechanism(s) of ESI-MS, the relations between tertiary structures in solution and charge structures of macro-ions in the gas phase, and experimental preconditions for the identification of noncovalent complexes are described. The hitherto successful applications to the identification of enzyme–substrate and –inhibitor complexes, supramolecular protein–and protein–nucleotide complexes, double-stranded polynucleotides, as well as synthetic self-assembled complexes demonstrate broad potential for the direct analysis of specific noncovalent interactions. The present results suggest new applications for the characterization of supramolecular structures and molecular recognition processes that previously have not been amenable to mass spectrometry; for example, the sequence-specific oligomerization of polypeptides, antigen–antibody complexes, enzyme–and receptor–ligand interactions, and the evaluation of molecular specificity in combinatorial syntheses and self-assembled systems.