Cooperativity, partially bound states, and enthalpy-entropy compensation

Efforts to develop a quantitative understanding of molecular recognition rely on the additivity of individual intermolecular interactions, and cooperativity represents one of the major potential stumbling blocks. A chemical double-mutant cycle has been used to experimentally measure cooperativity between functional group interactions within a complex framework. The interaction between two aromatic groups varies by 0.2 +/- 0.4 kJ mol(-1) in synthetic H-bonded complexes that differ by 8-13 kJ mol(-1) in overall stability. In these systems, the free energies associated with individual intermolecular interactions can therefore be reliably treated in an additive fashion. The results suggest that alternative explanations should be considered for cooperative phenomena observed in other systems, and a rationale based on the population of partially bound states in flexible molecules is proposed to account for the enthalpic chelate effect and enthalpy-entropy compensation.     

A magnetic iron(III) switch with controlled and adjustable thermal response for solution processing

Spin crossover requires cooperative behavior of the metal centers in order to become useful for devices. While cooperativity is barely predictable in solids, we show here that solution processing and the covalent introduction of molecular recognition sites allows the spin crossover of iron(III) sal(2)trien complexes to be rationally tuned. A simple correlation between the number of molecular recognition sites and the spin crossover temperature enabled the fabrication of materials that are magnetically bistable at room temperature. The predictable behavior relies on combining function (spin switching) and structure (supramolecular assembly) through covalent interactions in a single molecular building block.     

pH responsiveness of dendrimer-like poly(ethylene oxide)s

Poly(ethylene oxide) (PEO) and poly(acrylic acid) (PAA), two polymers known to form pH-sensitive aggregates through noncovalent interactions, were assembled in purposely designed architecture -a dendrimer-like PEO scaffold carrying short inner PAA chains-to produce unimolecular systems that exhibit pH responsiveness. Because of the particular placement of the PAA chains within the dendrimer-like structure, intermolecular complexation between acrylic acid (AA) and ethylene oxide (EO) units-and thus macroscopic aggregation or even mesoscopic micellization-could be avoided in favor of the sole intramolecular complexation. The sensitivity of such interactions to pH was exploited to generate dendrimer-like PEOs that reversibly shrink and expand with the pH. Such PAA-carrying dendrimer-like PEOs were synthesized in two main steps. First, a fifth-generation dendrimer-like PEO was obtained by combining anionic ring-opening polymerization (AROP) of ethylene oxide from a tris-hydroxylated core and selective branching reactions of PEO chain ends. To this end, an AB(2)C-type branching agent was designed: the latter includes a chloromethyl (A) group for its covalent attachment to the arm ends, two geminal hydroxyls (B(2)) protected in the form of a ketal ring for the growth of subsequent PEO generations by AROP, and a vinylic (C) double bonds for further functionalization of the interior of dendrimer-like PEOs. Reiteration of AROP and derivatization of PEO branches allowed us to prepare a dendrimer-like PEO of fourth generation with a total molar mass of 52,000 g x mol(-1), containing 24 external hydroxyl functions and 21 inner vinylic groups in the interior. A fifth generation of PEO chains was generated from this parent dendrimer-like PEO of fourth generation using a "conventional" AB(2)-type branching agent, and 48 PEO branches could be grown by AROP. The 48 outer hydroxy-end groups of the fifth-generation dendrimer-like PEO obtained were subsequently quantitatively converted into inert benzylic groups using benzyl bromide. The 21 internal vinylic groups carried by the PEO scaffold were then chemically modified in a two-step sequence into bromoester groups. The latter which are atom transfer radical polymerization (ATRP) initiating sites thus served to grow poly(tert-butylacrylate) chains. After a final step of hydrolysis of the tert-butyl ester groups, double, hydrophilic, dendrimer-like PEOs comprising 21 internal junction-attached poly(acrylic acid) (PAA) blocks could be obtained. Dynamic light scattering was used to determine the size of these dendrimer-like species in water and to investigate their response to pH variation: in particular, how the pH-sensitive complexation of EO and AA units affects their overall behavior.     

Double-stranded helices and molecular zippers assembled from single-stranded coordination polymers directed by supramolecular interactions

Using three nonlinear dicarboxylates, isophthalate (ipa), 4,4'-oxybis(benzoate) (oba), and ethylenedi(4-oxybenzoate) (eoba), we have prepared five neutral infinite copper(II) dicarboxylate coordination polymers containing lateral aromatic chelate ligands, namely [Cu(ipa)(2,2'-bpy)]n.2nH2O (1), [Cu2(ipa)2(phen)2H2O]n (2), [Cu(oba)(phen)]n (3), [Cu(oba)(2,2'-bpy)]n (4), and [Cu(eoba)(phen)]n (5; 2,2'-bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline) by hydrothermal synthesis. X-ray single-crystal structural analyses of these complexes reveal that the nonlinear flexible or V-shaped dicarboxylates can induce the helicity or flexuousity of the polymeric chains and aromatic chelate ligands are important in providing potential supramolecular recognition sites for pi-pi aromatic stacking interactions. An appropriate combination of the bridging dicarboxylate and aromatic chelate can induce a pair of single-stranded helical or flexuous chains to generate a double-stranded helix or molecular zipper through supramolecular interactions, respectively.     

Stepwise effective molarities in porphyrin oligomer complexes: preorganization results in exceptionally strong chelate cooperativity

Complexes of zinc porphyrin oligomers with multivalent ligands can be denatured by adding a large excess of a monodentate ligand, such as quinuclidine. We have used denaturation titrations to determine the stabilities of the complexes of a cyclic zinc-porphyrin hexamer with multidentate ligands with two to six pyridyl coordination sites. The corresponding complexes of linear porphyrin oligomers were also investigated. The results reveal that the stepwise effective molarities (EMs) for the third through sixth intramolecular coordination events with the cyclic hexamer are extremely high (EM = 10(2)-10(3) M), whereas the values for the linear porphyrin oligomers are modest (EM ≈ 0.05 M). The speciation profiles for the denaturation reactions demonstrate that intermediate species are not significantly populated and that these equilibria are well described by a highly cooperative two-state model.     

Opposing Phase‐Segregation and Hydrogen‐Bonding Forces in Supramolecular Polymers

Phase segregation between different macromolecules and specific weak interactions are the basis of molecular organization in many biological systems, which are held together by attractive hydrogen bonds (H‐bonds) and dissociated by phase segregation. We report significant changes in the association behavior of covalent H‐bonds by the phase of attached polymer chains. Depending on the aggregation state, we observed either intact H‐bonds despite segregation of the phases, or macrophase separation with a larger amount of H‐bonding dissociation.     

Very Long‐Range Effects: Cooperativity between Anion–π and Hydrogen‐Bonding Interactions

The interplay between two important non‐covalent interactions involving aromatic rings (namely anion–π and hydrogen bonding) is investigated. Very interesting cooperativity effects are present in complexes where anion–π and hydrogen bonding interactions coexist. These effects are found in systems where the distance between the anion and the hydrogen‐bond donor/acceptor molecule is as long as ～11 Å. These effects are studied theoretically using the energetic and geometric features of the complexes, which were computed using ab initio calculations. We use and discuss several criteria to analyze the mutual influence of the non‐covalent interactions studied herein. In addition we use Bader’s theory of atoms‐in‐molecules to characterize the interactions and to analyze the strengthening or weakening of the interactions depending upon the variation of the charge density at the critical points.     

Allosteric and Chelate Cooperativity in Divalent Crown Ether/Ammonium Complexes with Strong Binding Enhancement

A thorough thermodynamic analysis by isothermal titration calorimetry of allosteric and chelate cooperativity effects in divalent crown ether/ammonium complexes is combined with DFT calculations including implicit solvent on the one hand and large‐scale molecular dynamics simulations with explicit solvent molecules on the other. The complexes studied exhibit binding constants up to 2×10⁶ m ^?1 with large multivalent binding enhancements and thus strong chelate cooperativity effects. Slight structural changes in the spacers, that is, the exchange of two ether oxygen atoms by two isoelectronic methylene groups, cause significantly stronger binding and substantially increased chelate cooperativity. The analysis is complemented by the examination of solvent effects and allosteric cooperativity. Such a detailed understanding of the binding processes will help to efficiently design and construct larger supramolecular architectures with multiple multivalent building blocks.     

First dicyanamide-bridged spin-crossover coordination polymer: synthesis, structural, magnetic, and spectroscopic studies

We report here on the synthesis and characterisation of a first iron(II) spin-crossover coordination polymer with the dca spacer ligand, having the formula [Fe(aqin)2(dca)]ClO4.MeOH (aqin=8-aminoquinoline, dca=dicyanamide), which displays a two-step complete spin transition. Variable-temperature magnetic susceptibility measurements and M?ssbauer spectroscopy have revealed that the two relatively gradual steps are centred at 215 and 186 K and are separated by an inflection point at about 201 K, at which 50 % of the complex molecules undergo a spin transition. The two steps are related to the existence of two crystallographically inequivalent metal sites, as confirmed by the structural and M?ssbauer studies. The crystal structure was resolved at 293 K (HS form) and 130 K (LS form). Both spin-state structures belong to the triclinic P1 space group (Z=2). The complex assumes a linear chain structure, in which the active iron(II) sites are linked to each other by anionic dicyanamide ligands acting as chemical bridges. The Fe-Fe distances through the dca ligand are 8.119(1) and 7.835(1) A in the high-spin and low-spin structures, respectively. The polymeric chains extend along a (1, 0, -1) axis and are packed in sheets, between which the perchlorate anions and methanol molecules are inserted. The complex molecules are linked together by pi-stacking interactions and H-bonding between the H-donor aqin ligands and the perchlorate ions. These structural features provide a basis for cooperative interactions in the crystal lattice. Analysis of the two-step spin-crossover character in this compound suggests that covalent interactions through the spacer ligand do not provide the main mechanism of cooperativity.     

Quantifying the role of water in protein-carbohydrate interactions

Water-mediated interactions play a key role in carbohydrate-lectin binding, where the interactions involve a conserved water that is separated from the bulk solvent and present a bridge between the side chains of the protein and the carbohydrate ligand. To apply quantum mechanical methods to examine the role of conserved waters, we present an analysis in which the relevant carbohydrate atoms are modeled by methanol, and in which the protein is replaced by a limited number of amino acid side chains. Clusters containing a conserved water and a representative amino acid fragment were also examined to determine the influence of amino acid side chains on interaction energies. To quantify the differential binding energies of methanol versus water, quantum mechanical calculations were performed at the B3LYP/6-311++G(3df,3pd)//B3LYP/6-31+G(d) level in which either a methanol molecule was bound to the conserved water (liganded state) or in which a water molecule replaces the methanol (unliganded state). Not surprisingly, the binding of a water to clusters containing charged amino acid side chains was more favorable by 1.55 to 7.23 kcal/mol than that for the binding of a water to the corresponding pure water clusters. In contrast, the binding energy of water to clusters containing polar-uncharged amino acid side chains ranged from 4.35 kcal/mol less favorable to 4.72 kcal/mol more favorable than for binding to the analogous pure water clusters. The overall trend for the binding of methanol versus water, in any of the clusters, favored methanol by an average value of 1.05 kcal/mol. To extend these studies to a complex between a protein (Concanavalin A) and its carbohydrate ligand, a cluster was examined that contained the side chains of three key amino acids, namely asparagine, aspartate, and arginine, as well as a key water molecule, arranged as in the X-ray diffraction structure of Con A. Again, using methanol as a model for the endogenous carbohydrate ligand, energies of -5.94 kcal/mol and -5.70 kcal/mol were obtained for the binding of methanol and water, respectively, to the Con A-water cluster. The extent to which cooperativity enhanced the binding energies has been quantified in terms of nonadditive three-body contributions. In general, the binding of water or methanol to neutral dimers formed cooperative clusters; in contrast, the cooperativity in charged clusters depended on the overall geometry as well as the charge.     

Crystal packing of TCNQ anion pi-radicals governed by intermolecular covalent pi-pi bonding: DFT calculations and statistical analysis of crystal structures

On the basis of a thorough Cambridge Structural Database survey, we present a statistical analysis of the packing of TCNQ anion pi-radicals in TCNQ charge transfer salts, which reveals three packing motifs between neighboring TCNQs: one with a zero longitudinal offset and an approximate 1 A transversal offset, another with an approximate 2 A longitudinal offset and zero transversal offset, and the third with a relatively long sigma-bond in the length of r = 1.6-1.7 A connecting two TCNQ fragments. Along with the statistical analysis of the crystal structures, we also present density functional theory calculations of the total energy, covalent pi-pi bonding interaction energy, and Coulombic repulsion energy for the [TCNQ](2)(2-)pi-dimers with various packing geometries. We find that the interactions between TCNQ anion pi-radicals include contributions from intermolecular covalent pi-pi bonding interaction and local dipole repulsions, in addition to Coulombic repulsion, van der Waals and the attractive electrostatic forces between counter-cations and TCNQ anions pointed out recently by other groups for TCNE anion radicals. We describe an approximate formula for intermolecular interaction energy, E(int) = E(coul) + E(bond) + E(vdW), for systems in vacuum, while in the solid state E(coul) is compensated by the attractive electrostatic forces between counter-cations and TCNQ anions. We conclude that the crystal packing of TCNQ molecules in their charge transfer salts is predominantly determined by the intermolecular covalent pi-pi bonding term, E(bond).     

Linear chain aluminium(III) carboxymethylphosphonate with encapsulated ammonium ions

An aluminium carboxymethylphosphonate of composition (NH(4))(2)Al(H(1/2)O(3)PCH(2)CO(2))(2) has been prepared hydrothermally. The aluminium cation is chelated by six membered rings formed from bonding by both the carboxylate and phosphonate oxygens. These chelate rings in turn form larger eight membered rings by connecting to similar chelate groups to form chains running along the a-axis.     

Cooperativity in hydrogen-bonded interactions: ab initio and "atoms in molecules" analyses

The H(2)CO...(HF)(n) (n = 1, ..., 9) complexes were investigated using the MP2 method and the following basis sets: 6-311++G(d,p), aug-cc-pVDZ and aug-cc-pVTZ. It was found that the cooperativity effect enhances significantly the F-H...O hydrogen bond; in some of cases one can detect the covalent nature of hydrogen bonding. To deepen the nature of the interactions investigated, the scheme of decomposition of the interaction energy was applied; for stronger H-bonds where the cooperativity is more important, the delocalization energy term increases. The ratio of delocalization energy to electrostatic energy increases for stronger hydrogen bonds where the proton...acceptor distance is shorter. The Bader theory was also applied, and it was found that for stronger H-bonds the electronic energy density at the proton...acceptor bond critical point is negative and may be attributed to the partly covalent interaction.     

Rapid Evaluation of Individual Hydrogen Bonding Energies in Linear Water Chains

A model is proposed to rapidly evaluate the individual hydrogen bonding energies in linear water chains. We regarded the two O--H bonds of a water molecule as two dipoles. The magnitude of the O--H bond dipole mo- ment can be varied due to the other water molecules＇ presence. An analytic potential energy function, which explicitly contains the permanent dipole-dipole interactions, the polarization interactions, the van der Waals interactions and the covalent interactions, was therefore established. The individual hydrogen bonding energies in a series of linear water chains were evaluated via the analytic potential energy function and compared with those obtained from the CP-corrected MP2/aug-cc-pVTZ calculations. The results show that the analytic potential energy function not only can produce the individual hydrogen bonding energies as accurately as the CP-corrected MP2/aug-cc-pVTZ method, but is very efficient as well, demonstrating the model proposed is reasonable and useful. Based on the individual hy- drogen bonding energies obtained, the hydrogen bonding cooperativity in the linear water chains was explored and the natures of the hydrogen bonding in these water chains were discussed.     

Achieving Strong Positive Cooperativity through Activating Weak Non‐Covalent Interactions

Positive cooperativity achieved through activating weak non‐covalent interactions is common in biological assemblies but is rarely observed in synthetic complexes. Two new molecular tubes have been synthesized and the syn isomer binds DABCO‐based organic cations with high orientational selectivity. Surprisingly, the ternary complex with two hosts and one guest shows a high cooperativity factor (α=580), which is the highest reported for synthetic systems without involving ion‐pairing interactions. The X‐ray single‐crystal structure revealed that the strong positive cooperativity likely originates from eight C?H???O hydrogen bonds between the two head‐to‐head‐arranged syn tube molecules. These relatively weak hydrogen bonds were not observed in the free hosts and only emerged in the complex. Furthermore, this complex was used as a basic motif to construct a robust [2+2] cyclic assembly, thus demonstrating its potential in molecular self‐assembly.     

A theoretical study of beta-sheet models: is the formation of hydrogen-bond networks cooperative?

The cooperativity in terms of enthalpy contribution for beta-sheet formation of polyglycine models in a vacuum has been studied theoretically by using a repeating unit approach. No cooperativity is found in the parallel direction for both the parallel and antiparallel beta-sheets. Cooperativity in the perpendicular direction is dependent upon the residue number (m) in each beta-strand. While there is large cooperativity in the acetamide hydrogen-bond chain (m = 0), the cooperativity is not large in beta-sheet networks (m > 0). SCIPCM solvent model calculations also significantly reduce the cooperativity in hydrogen-bond chains. It is concluded that cooperativity is mainly due to long-range electrostatic interactions and not due to the resonance effect.     

REPAIR OF NEAR-VISIBLE- and BLUE-LIGHT-INDUCED DNA SINGLE-STRAND BREAKS BY THE CHO CELL LINES AA8 and EM9

The induction of single-strand breaks (SSB) and the kinetics of SSB repair were measured in two Chinese hamster ovary cell lines irradiated with monochromatic photons of near-visible radiation (405 nm) and blue light (434 nm). The radiosensitive and UV-A-sensitive mutant line EM9 is known to repair SSB induced by ionizing radiation or 365-nm UV-A more slowly than the parent line AA8. At the 10% survival level, EM9 cells were 1.7- and 1.6-fold more sensitive than AA8 cells to 405 and 434 nm radiation, respectively. This sensitivity was not due to differences in induction of SSB because AA8 and EM9 cells accumulated the same number of initial breaks when irradiated at 0.5 degrees C with either 405 nm (5.9 SSB per MJ/m2) or 434 nm (5.1 SSB per MJ/m2), as measured by alkaline elution. When the cells repaired these SSB at 37 degrees C in full culture medium, biphasic repair kinetics were observed for both cell lines. In both phases of repair, EM9 cells repaired breaks induced by both wavelengths more slowly than did AA8 cells. The t1/2 values for the repair phases for 405-nm-induced SSB were 3.8 and 150 min for EM9, and 1.5 and 52 min for AA8; the corresponding values for repair of 434 nm breaks were 3.7 and 39 min for EM9, and 2.0 and 30 min for AA8. Because of this slower repair, EM9 cells left more SSB unrepaired after 90 min than did AA8 cells for both wavelengths.(ABSTRACT TRUNCATED AT 250 WORDS)     

Applications of dynamic combinatorial chemistry for the determination of effective molarity

A new strategy for determining thermodynamic effective molarities (EM) for macrocylisation reactions using dynamic combinatorial chemistry under dilute conditions is presented. At low concentrations, below the critical value, Dynamic Libraries (DLs) of bifunctional building blocks contain only cyclic species, so it is not possible to quantify the equilibria between linear and cyclic species. However, addition of a monofunctional chain stopper can be used to promote the formation of linear oligomers allowing measurement of EM for all cyclic species present in the DL. The effectiveness of this approach was demonstrated for DLs generated from mixtures of 1,3-diimine calix[4]arenes, linear diaminoalkanes and monoaminoalkanes. For macrocycles deriving from one bifunctional calixarene and one diamine, there is an alternating pattern of EM values with the number of methylene units in the diamine: odd numbers give significantly higher EMs than even numbers. For odd numbers of methylene units, the alkyl chain can adopt an extended all anti conformation, whereas for even numbers of methylene units, gauche conformations are required for cyclisation, and the associated strain reduces EM. The value of EM for the five-carbon linker indicates that this macrocycle is a strainless ring.