Distinction and Quantification of Noncovalent Dispersive and Hydrophobic Effects.

The possibilities of comparing computational results of noncovalent interactions with experimental data are discussed, first with respect to intramolecular interactions. For these a variety of experimental data such as heats of formation, crystal sublimation heats, comparison with energy minimized structures, and spectroscopic data are available, but until now largely have not found widespread application. Early force field and QM/MP2 calculations have already shown that the sublimation heats of hydrocarbons can be predicted with an accuracy of ±1%. Intermolecular interactions in solution or the gas phase are always accompanied by difficult to compute entropic contributions, like all associations between molecules. Experimentally observed T∆S values contribute 10% to 80% of the total ∆G, depending on interaction mechanisms within the complexes, such as, e.g., hydrogen bonding and ion pairing. Free energies ∆G derived from equilibrium measurements in solution allow us to define binding increments ∆∆G, which are additive and transferable to a variety of supramolecular complexes. Data from more than 90 equilibrium measurements of porphyrin receptors in water indicate that small alkanes do not bind to the hydrophobic flat surfaces within a measuring limit of ∆G = ±0.5 kJ/mol, and that 20 functions bearing heteroatoms show associations by dispersive interactions with up to ∆G = 8 kJ/mol, roughly as a function of their polarizability. Aromatic systems display size-dependent affinities ∆G as a linear function of the number of π-electrons.

Strain effects determine the performance of artificial allosteric systems: calixarenes as models.

It is shown that the performance of allosteric systems regarding the efficiency and the speed of response depends critically on the strain energy of the equilibrating conformers and of the corresponding interconversion transition state. The affinity of a substrate A can be large enough to overcome in the absence of an effector E by induced fit the strain involved in the formation of an optimal conformation for binding A. The efficiency as given by the ratio KAE/KA of binding constants in the presence or absence of an effector is, for many published synthetic allosteric systems, relatively low; in practice this means that these only function within rather limited concentration ranges. A small KAE/KA ratio means that the binding strength of A or the corresponding signal will increase only little by adding an effector, and may need higher concentration of E. Implementation of steric distortion in the minor conformer can lead to reduced binding of A in the absence of the effector E. Destabilization of conformers can also result from the inclusion of high energy water molecules within a cavity. Furthermore, until now it has been overlooked that strain in the transition state can lead to reaction times of up to days, and thus to the neglect of experimental observation. The role of conformational changes within an allosteric molecule is characterized with a variety of calixarenes and other compound classes, offering a clue for the design of more efficient synthetic systems with high cooperativity.

Logic-Gate Functions in Chemomechanical Materials.

Chemomechanical polymers that change their shape or volume on stimulation by multiple external chemical signals, particularly on the basis of selective molecular recognition, are discussed. Several examples illustrate how such materials, usually in the form of hydrogels, can be used for the design of chemically triggered valves or artificial muscles and applied, for example, in self-healing materials or drug delivery. The most attractive feature of such materials is that they can combine sensor and actuator within single units, from nano- to macrosize. Simultaneous action of a cofactor allows selective response in the sense of AND logic gates by, for example, amino acids and peptides, which without the presence of a second effector do not induce any changes.

Spatial mismatch, non-additive binding energies and selectivity in supramolecular complexes.

The consequences of spatial mismatch between a receptor and ligand on affinity and selectivity of supramolecular complexes are illustrated with several examples. Conformationally rigid complexes and shorter-range non-covalent forces are characterized by large affinity changes, in contrast to more flexible systems. In the most frequent complexes with several spaciously separated binding sites, the additivity of binding energies and the correlation between affinity and selectivity is often lost by partial mismatch. Complete changes of binding modes and preferences can be the consequence, as illustrated particularly with cyclodextrin complexes. Associations with biopolymers, which usually depend also on several interaction sites, rarely show affinity-selectivity correlations, particularly not for high-affinity drug-receptor interactions. The negative consequences of spatial mismatch can be reduced by the introduction of flexible linkers between one binding site which secures affinity and the other one responsible for selectivity.

Efficiency parameters in artificial allosteric systems.

It is shown that the until now largely overlooked change of the conformational energy ΔGC is the dominating factor for most synthetic allosteric complexes. Essential is the energy ΔGC required for the formation of a suitable geometry for ligand binding in the absence of an effector molecule E; ΔGC is usually dominated by an increase of strain and/or by high energy solvents in a cavity. The role of the effector molecule E in such systems is to generate a suitable conformation for binding the ligand A and thus to compensate the unfavourable conformational energy ΔGC. Positive cooperativity increases with ΔGC, and decreases with the ΔG0(A) value which reflects the binding energy of A in a strain-free host. As illustrated with a few examples ΔG0(A) cannot be measured directly but can eventually be estimated independently. Many artificial allosteric systems described in the literature, such as those based on ethylene glycol chains or bipyridyl units, lack significant strain differences, and are therefore less efficient. Negative cooperativity is determined only by the difference ΔΔGA,E between the binding energies at the two sites; it can be enhanced or lowered by concomitant changes in ΔGC.

Experimental Binding Energies in Supramolecular Complexes.

On the basis of many literature measurements, a critical overview is given on essential noncovalent interactions in synthetic supramolecular complexes, accompanied by analyses with selected proteins. The methods, which can be applied to derive binding increments for single noncovalent interactions, start with the evaluation of consistency and additivity with a sufficiently large number of different host-guest complexes by applying linear free energy relations. Other strategies involve the use of double mutant cycles, of molecular balances, of dynamic combinatorial libraries, and of crystal structures. Promises and limitations of these strategies are discussed. Most of the analyses stem from solution studies, but a few also from gas phase. The empirically derived interactions are then presented on the basis of selected complexes with respect to ion pairing, hydrogen bonding, electrostatic contributions, halogen bonding, π-π-stacking, dispersive forces, cation-π and anion-π interactions, and contributions from the hydrophobic effect. Cooperativity in host-guest complexes as well as in self-assembly, and entropy factors are briefly highlighted. Tables with typical values for single noncovalent free energies and polarity parameters are in the Supporting Information.

Unwinding DNA and RNA with Synthetic Complexes: On the Way to Artificial Helicases.

Synthetic helicases can be designed on the basis of ligands that bind more strongly to single-stranded nucleic acids than to double-stranded nucleic acids. This can be achieved with ligands containing phenyl groups, which intercalate into single strands, but due to their small size not into double strands. Moreover, two phenyl rings are combined with a distance that allows bis-intercalation with only single strands and not double strands. In this respect, such ligands also mimic single-strand binding (SSB) proteins. Exploration with more than 23 ligands, mostly newly synthesised, shows that the distance between the phenyl rings and between those and the linker influence the DNA unwinding efficiency, which can reach a melting point decrease of almost ΔTm =50 °C at much lower concentrations than that with any other known artificial helicases. Conformational pre-organisation of the ligand plays a decisive role in optimal efficiency. Substituents at the phenyl rings have a large effect, and increase, for example, in the order of H

Dispersive interactions in solution complexes.

Dispersive interactions are known to play a major role in molecular associations in the gas phase and in the solid state. In solution, however, their significance has been disputed in recent years on the basis of several arguments. A major problem until now has been the separation of dispersive and hydrophobic effects, which are both maximized in water due the low polarizability of this most important medium. Analyses of complexes between porphyrins and systematically varied substrates in water have allowed us to discriminate dispersive from hydrophobic effects, as the latter turned out to be negligible for complexations with flat surfaces such as porphyrins. Also, for the first time, it has become possible to obtain binding free energy increments ΔΔG for a multitude of organic residues including halogen, amide, amino, ether, carbonyl, ester, nitro, sulfur, unsatured, and cyclopropane groups, which turned out to be additive. Binding contributions for saturated residues are unmeasurably small, with ΔΔG > 1 kJ/mol, but they increase to, e.g., ΔΔG = 5 kJ/mol for a nitro group, a value not far from, e.g., that of a stacking pyridine ring. Stacking interactions of heteroarenes with porphyrins depend essentially on the size of the arenes, in line with polarizabilities, and seem to be rather independent of the position of nitrogen within the rings. Measurements of halogen derivatives indicate that complexes with porphyrins, cyclodextrins, and pillarenes as hosts in different media consistently show increasing stability from fluorine to iodine as the substituent. This, and the observed sequence with other substrates, is in line with the expected increase in dispersive forces with increasing polarizability. Induced dipoles, which also would increase with polarizability, can be ruled out as providing the driving source in view of the data with halides: the observed stability sequence is opposite the change of electronegativity from fluorine to iodine. The same holds for the solvent effect observed in ethanol-water mixtures. Dispersive contributions vary not only with the polarizability of the used media but also with the interacting receptor sites; it has been shown that for cucurbiturils the polarizability inside the cavity is extremely low, which also explains why hydrophobic effects are maximized with these hosts. Complexations with other known host compounds, however, such as those between cryptands or cavitands with, e.g., noble gases, bear the signature of dominating dispersive forces. Some recent examples illustrate that such van der Waals forces can also play an important role in complexations with proteins. Again, a clue for this is the increase in ΔG for inhibitor binding by 7 kJ/mol for, e.g., a bromine in comparison to a fluorine derivative.

Limitations and extensions of the lock-and-key principle: differences between gas state, solution and solid state structures.

The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock-and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed.

The hydrophobic effect revisited--studies with supramolecular complexes imply high-energy water as a noncovalent driving force.

Traditional descriptions of the hydrophobic effect on the basis of entropic arguments or the calculation of solvent-occupied surfaces must be questioned in view of new results obtained with supramolecular complexes. In these studies, it was possible to separate hydrophobic from dispersive interactions, which are strongest in aqueous systems. Even very hydrophobic alkanes associate significantly only in cavities containing water molecules with an insufficient number of possible hydrogen bonds. The replacement of high-energy water in cavities by guest molecules is the essential enthalpic driving force for complexation, as borne out by data for complexes of cyclodextrins, cyclophanes, and cucurbiturils, for which complexation enthalpies of up to -100 kJ mol(-1) were reached for encapsulated alkyl residues. Water-box simulations were used to characterize the different contributions from high-energy water and enabled the calculation of the association free enthalpies for selected cucurbituril complexes to within a 10% deviation from experimental values. Cavities in artificial receptors are more apt to show the enthalpic effect of high-energy water than those in proteins or nucleic acids, because they bear fewer or no functional groups in the inner cavity to stabilize interior water molecules.

Supramolecular complexations of natural products.

Complexations of natural products with synthetic receptors as well as the use of natural products as host compounds are reviewed, with an emphasis on possible practical uses or on biomedical significance. Applications such as separation, sensing, enzyme monitoring, and protection of natural drugs are first outlined. We then discuss examples of complexes with all important classes of natural compounds, such as amino acids, peptides, nucleosides/nucleotides, carbohydrates, catecholamines, flavonoids, terpenoids/steroids, alkaloids, antibiotics and toxins.

Interactions in supramolecular complexes involving arenes: experimental studies.

The process of learning by doing has fueled supramolecular chemistry and, more specifically, the understanding of noncovalent aromatic interactions in synthetic and natural systems. The preparation of new host molecules and the investigation of their complexations have produced many insights into significant noncovalent binding mechanisms. In this Account, we attempt to discuss significant binding contributions involving aromatic units and their practical applications. We use typical examples from our group and the literature, but this Account is not a comprehensive view of the field. Other than systems with saturated frameworks, host compounds based on arenes offer better controlled conformations and active interactions with many guest molecules. Because of their fluorescent properties, larger aryl systems are particularly suitable for sensors. The noncovalent interactions observed with different supramolecular complexes can be compared and exploited for interactions with biopolymers such as nucleic acids. Complexes formed with cyclophanes have been a constant source of inspiration for understanding noncovalent forces and their use for the design of functional supramolecular systems. Other than cyclodextrins or ionophores, which occur in nature, arene-based macrocycles are synthetic and provide more opportunities for structural variations than other macrocycles. These derivatives allow researchers to study and to exploit an unusually broad variety of binding mechanisms in both aqueous and organic media. Systematic analyses of complexes with different substituents and structures in solution, based also on flat aromatic systems such as porphyrins, can lead to a consistent picture of the noncovalent forces that dominate in these systems. These studies have elucidated attractive interactions between many heteroatoms and π systems including cyclopropanes . Through systematic analysis of the equilibrium measurements one can derive binding free energy increments for different interactions. The increments are usually additive and provide predictive tools for the design of new supramolecular systems, benchmarks for computational approaches, and an aid for drug design. In aqueous media, the major noncovalent forces between different aryl systems or between arenes and heteroatoms of larger polarizibility are dispersive, and hydrophobic forces play a minor role. In several examples, we show that electrostatic forces also contribute significantly if donor and acceptor groups show complimentarity. In early investigations, researchers found cation-π and, to a lesser degree, anion-π interactions with several cyclophanes in systems where the host or the guest molecules bear charges in an orientation that facilitates contact between charged and aryl portions of the molecules. In supramolecular complexes, hydrogen bonding effects are usually only visible in apolar media, but very strong acceptors such as phenolate anions can also work in water. To facilitate potential applications, researchers have primarily developed water-soluble, arene-containing receptors through the implementation of permanent charges. Supramolecular complexes that mimic enzymes can also rely on aryl interactions. Examples in this Account illustrate that the conformation of host-guest complexes may differ significantly between the solid and solution state, and suitable spectroscopic methods are needed to observe and control these conformations.

Supramolecular complexation for environmental control.

Supramolecular complexes offer a new and efficient way for the monitoring and removal of many substances emanating from technical processes, fertilization, plant and animal protection, or e.g. chemotherapy. Such pollutants range from toxic or radioactive metal ions and anions to chemical side products, herbicides, pesticides to drugs including steroids, and include degradation products from natural sources. The applications involve usually fast and reversible complex formation, due to prevailing non-covalent interactions. This is of importance for sensing as well as for separation techniques, where the often expensive host compounds can then be reused almost indefinitely. Immobilization of host compounds, e.g. on exchange resins or on membranes, and their implementation in smart new materials hold particular promise. The review illustrates how the design of suitable host compounds in combination with modern sensing and separation methods can contribute to solve some of the biggest problems facing chemistry, which arise from the everyday increasing pollution of the environment.

Supramolecular interactions in chemomechanical polymers.

Molecular recognition is the basis for the operation of most biological functions; outside of nature, it has also been developed to a high degree of sophistication within the framework of supramolecular chemistry. More recently, selective noncovalent interactions, which constitute molecular recognition, are being used in intelligent new materials that transform chemical signals into actions, such as the release of drugs. The presence of supramolecular binding sites allows chemomechanical polymers to operate as sensors and actuators within a single unit without the need for any additional devices such as transducers or power supplies. A polymer can be designed so that a particular chemical substance, most often in aqueous surroundings, will trigger either a large expansion or a large contraction, depending on the mechanism. The translation of binding energy into mechanical motion can, with a suitable arrangement of the materials in tubes or on flexible films, be harnessed for unidirectional drives, flow control, the liberation of drugs, or the uptake of toxic compounds, among other applications. Miniaturization of the polymer particles allows one to enhance both the sensitivity and speed of the response, which is of particular importance in sensing. The basis for the selective response to external effector compounds, such as metal ions, amino acids, peptides, or nucleotides, is their noncovalent interaction with complementary functions covalently bound to the polymer network. With suitable polymers, selectivity between structural isomers, and even between enantiomers, as triggers can be achieved. As with supramolecular complexes in solution, the underlying interactions in polymers comprise a variety of noncovalent binding mechanisms, which are not easy to distinguish and quantify, and more so with polymers that are not monodisperse. In this Account, we present systematic comparisons of different polymers and effector classes that allow, for the first time, the characterization of these contributions in chemomechanical polymers: they comprise ion pairing, metal coordination, stacking, cation-pi, dispersive, and hydrophobic forces. In contrast, hydrogen bonding has a major role primarily in the hydrogel network structure itself. The fully reversible polymer volume changes are essentially determined by water uptake or release. In gels derived from boronic acid, glucose can serve as a cross-linking effector in promoting contractions via strong, reversible covalent bond formation in a highly distinctive manner. Cooperativity between two different effector compounds is more frequently seen with such polymers than in solution: it leads to logical AND gates by different motions of the particles, with a direct communication link to the outside world. For example, with a polymer that bears several recognition sites, triggering peptides induce motion only if Zn(2+) or Cu(2+) ions are simultaneously present. The molecular recognition mechanisms that cause volume changes in polymers share similarities with extensively studied supramolecular systems in solution, but there are also remarkable differences. In this Account, we bring the knowledge learned from solution studies to bear on our systematic analysis of polymeric systems in an effort to promote the effective harnessing of the forces involved in chemomechanical polymers and the smart materials that can be created with them.

Binding mechanisms in supramolecular complexes.

Supramolecular chemistry has expanded dramatically in recent years both in terms of potential applications and in its relevance to analogous biological systems. The formation and function of supramolecular complexes occur through a multiplicity of often difficult to differentiate noncovalent forces. The aim of this Review is to describe the crucial interaction mechanisms in context, and thus classify the entire subject. In most cases, organic host-guest complexes have been selected as examples, but biologically relevant problems are also considered. An understanding and quantification of intermolecular interactions is of importance both for the rational planning of new supramolecular systems, including intelligent materials, as well as for developing new biologically active agents.

Ligand binding to nucleic acids and proteins: Does selectivity increase with strength?

The possible relation of strength and selectivity of ligand binding to biomacromolecules and its theoretical limitation is discussed and illustrated with some examples. It is shown that a linear correlation between selectivity and affinity may be expected on the basis of thermodynamic principles, which also imply that multivalency is as important for selectivity as for affinity enhancement. That strictly linear correlations are often not observed is, apart form statistical problems, mostly due to interactions which may remain constant only at some sites but can differ significantly at other sites, which, e.g., dominate the affinity. Nevertheless, some drugs exhibit in line with theory at the same time a peak affinity and selectivity, such as etonitazene with different opioid receptors. Double-stranded nucleic acids feature relative stable and uniform structures and therefore show relatively good correlations with simple polyamines as ligands and RNA or DNA model receptors. Metalloproteins possess strong binding centers with additional discrimination sites, and can exhibit linear correlations, at least with structurally related metalloproteinases and their inhibitors.

Selectivity in supramolecular host-guest complexes.

The background of possible selectivity-affinity correlations and their limitations is reviewed, with typical crown ether and cryptand complexes, ionic associations, hydrogen bonded complexes and complexes driven by van der Waals, stacking or hydrophobic interactions, with some additional topics including associations based on metal coordination as supplementary material. This tutorial review is addressed to students and researchers interested in molecular recognition, and relates to the design of sensors, of discriminators for separation processes, of supramolecular devices and of drug compounds. A theoretical analysis of selectivity in supramolecular host-guest complexes, defined as a difference in binding free energies for structurally related guests, as a function of total binding free energy shows that for certain types of intermolecular interactions one may observe a correlation between selectivity and affinity. Such correlation fails however if the selectivity is due to additional interactions at a secondary binding sites, which is expected in complexes with anisotropic guest molecules. Several clear examples of theoretically expected selectivity-affinity correlations are found. The influence of reaction conditions on the experimentally observed selectivity, defined as a difference in complexation degrees with different guests in the presence of added receptor, is illustrated. The importance of often neglected solvent effects on selectivity is exemplified with ionophore and hydrogen bonded complexes.

Cooperativity and selectivity in chemomechanical polyethylenimine gels.

Gel particles obtained from polyethylenimine (PEI) cross-linked with 10% ethylene glycol diglycidyl ether show considerable selectivity in size changes if exposed to solutions of different effector compounds. Monocarboxylic acids induce contractions of, e.g., -9% for benzoate and -40% for 2-naphthoate (all values in one dimension such as length). With diacids, the contractions increase to -29% for 1,4-benzene and -68% for 2,6-naphthalene disulfonate, indicating the significant contributions of noncovalent ionic cross-linking and of interactions with aromatic residues. A striking cooperativity is observed if aromatic compounds such as naphthoic acid are used simultaneously with amino acids as effectors. The combination with, e.g., 2-naphthoic acid and phenylalanine induces, e.g., 69% contraction, whereas the single effector compounds induce only 40% and 8%, respectively. As expected with contraction of chemomechanical polymers, the kinetics of effector absorption is significantly slower than that of the size changes, which take, e.g., 5 min to reach one-half of the final contraction; with smaller gel particles, the rates are significantly increased. Gravimetric determinations show that release of solvation water is largely responsible for the observed volume contractions. Copper or zinc ions induce small contractions, also in experiments with PEI solutions, but show no evidence of cooperativity in combination with amino acids or peptides. MAS NMR spectra of the gels induced by aromatic effector compounds exhibited moderate upfield shifts of the polymer backbone signals, as a result of ring current effects.