Anion-Binding Properties of Short Linear Homopeptides.

A comprehensive thermodynamic and structural study of the complexation affinities of tetra (L1), penta (L2), and hexaphenylalanine (L3) linear peptides towards several inorganic anions in acetonitrile (MeCN) and N,N-dimethylformamide (DMF) was carried out. The influence of the chain length on the complexation thermodynamics and structural changes upon anion binding are particularly addressed here. The complexation processes were characterized by means of spectrofluorimetric, 1H NMR, microcalorimetric, and circular dichroism spectroscopy titrations. The results indicate that all three peptides formed complexes of 1:1 stoichiometry with chloride, bromide, hydrogen sulfate, dihydrogen phosphate (DHP), and nitrate anions in acetonitrile and DMF. In the case of hydrogen sulfate and DHP, anion complexes of higher stoichiometries were observed as well, namely those with 1:2 and 2:1 (peptide:anion) complexes. Anion-induced peptide backbone structural changes were studied by molecular dynamic simulations. The anions interacted with backbone amide protons and one of the N-terminal amine protons through hydrogen bonding. Due to the anion binding, the main chain of the studied peptides changed its conformation from elongated to quasi-cyclic in all 1:1 complexes. The accomplishment of such a conformation is especially important for cyclopeptide synthesis in the head-to-tail macrocyclization step, since it is most suitable for ring closure. In addition, the studied peptides can act as versatile ionophores, facilitating transmembrane anion transport.

Enhancing the Cation-Binding Ability of Fluorescent Calixarene Derivatives: Structural, Thermodynamic, and Computational Studies.

Novel fluorescent calix[4]arene derivatives L1 and L2 were synthesized by introducing phenanthridine moieties at the lower calixarene rim, whereby phenanthridine groups served as fluorescent probes and for cation coordination. To enhance the cation-binding ability of the ligands, besides phenanthridines, tertiary-amide or ester functionalities were also introduced in the cation-binding site. Complexation of the prepared compounds with alkali metal cations in acetonitrile (MeCN), methanol (MeOH), ethanol (EtOH), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) was investigated at 25 °C experimentally (UV spectrophotometry, fluorimetry, microcalorimetry, and in the solid state by X-ray crystallography) and by means of computational techniques (classical molecular dynamics and DFT calculations). The thermodynamic parameters (equilibrium constants and derived standard reaction Gibbs energies, reaction enthalpies, and entropies) of the corresponding reactions were determined. The tertiary-amide-based compound L1 was found to have a much higher affinity toward cations compared to ester derivative L2, whereby the stabilities of the ML1+ and ML2+ complexes were quite solvent-dependent. The stability decreased in the solvent order: MeCN ≫ EtOH > MeOH > DMF > DMSO, which could be explained by taking into account the differences in the solvation of the ligands as well as free and complexed alkali metal cations in the solvents used. The obtained thermodynamic quantities were thoroughly discussed regarding the structural characteristics of the studied compounds, as well as the solvation abilities of the solvents examined. Molecular and crystal structures of acetonitrile and water solvates of L1 and its sodium complex were determined by single-crystal X-ray diffraction. The results of computational studies provided additional insight into the L1 and L2 complexation properties and structures of the ligands and their cation complexes.

Anion-Sensing Properties of Cyclopentaphenylalanine.

Cyclic pentaphenylalanine was studied as an efficient anion sensor for halides, thiocyanate and oxoanions in acetonitrile and methanol. Stability constants of the corresponding complexes were determined by means of fluorimetric, spectrophotometric, 1H NMR, and microcalorimetric titrations. A detailed structural overview of receptor-anion complexes was obtained by classical molecular dynamics (MD) simulations. The results of 1H NMR and MD studies indicated that the bound anions were coordinated by the amide groups of cyclopeptide, as expected. Circular dichroism (CD) titrations were also carried out in acetonitrile. To the best of our knowledge, this is the first example of the detection of anion binding by cyclopeptide using CD spectroscopy. The CD spectra were calculated from the structures obtained by MD simulations and were qualitatively in agreement with the experimental data. The stoichiometry of almost all complexes was 1:1 (receptor:anion), except for dihydrogen phosphate where the binding of dihydrogen phosphate dimer was observed in acetonitrile. The affinity of the cyclopeptide receptor was correlated with the structure of anion coordination sphere, as well as with the solvation properties of the examined solvents.

The Role of Triazole and Glucose Moieties in Alkali Metal Cation Complexation by Lower-Rim Tertiary-Amide Calix[4]arene Derivatives.

The binding of alkali metal cations with two tertiary-amide lower-rim calix[4]arenes was studied in methanol, N,N-dimethylformamide, and acetonitrile in order to explore the role of triazole and glucose functionalities in the coordination reactions. The standard thermodynamic complexation parameters were determined microcalorimetrically and spectrophotometrically. On the basis of receptor dissolution enthalpies and the literature data, the enthalpies for transfer of reactants and products between the solvents were calculated. The solvent inclusion within a calixarene hydrophobic basket was explored by means of 1H NMR spectroscopy. Classical molecular dynamics of the calixarene ligands and their complexes were carried out as well. The affinity of receptors for cations in methanol and N,N-dimethylformamide was quite similar, irrespective of whether they contained glucose subunits or not. This indicated that sugar moieties did not participate or influence the cation binding. All studied reactions were enthalpically controlled. The peak affinity of receptors for sodium cation was noticed in all complexation media. The complex stabilities were the highest in acetonitrile, followed by methanol and N,N-dimethylformamide. The solubilities of receptors were greatly affected by the presence of sugar subunits. The medium effect on the affinities of calixarene derivatives towards cations was thoroughly discussed regarding the structural properties and solvation abilities of the investigated solvents.

Chloride-Assisted Peptide Macrocyclization.

The role of the Cl- anion as a templating agent for the synthesis of cyclopeptides was assessed through the preparation of three new homocyclolysines and other six cyclic peptides by head-to-tail lactamization. Isolated yields of products obtained by chloride-templating approach were considerably higher than those gained by a cation-promoted procedure, whereby, in some cases, only the anion-assisted synthesis yielded the desired cyclopeptides.

New Zinc Ion Parameters Suitable for Classical MD Simulations of Zinc Metallopeptidases.

The main aim of this work was to find parameters for the zinc ion in human dipeptidyl peptidase III (DPP III) active site that would enable its reliable modeling. Since the parameters publicly available failed to reproduce the zinc ion coordination in the enzyme, we developed a new set of the hybrid bonded/nonbonded parameters for the zinc ion suitable for molecular modeling of the human DPP III, dynamics, and ligand binding. The parameters allowed exchange of the water molecules coordinating the zinc ion and proved to be robust enough to enable reliable modeling not only of human DPP III and its orthologues but also of the other zinc-dependent peptidases with the zinc ion coordination similar to that in dipeptidyl peptidases III, i.e., peptidases with the zinc ion coordinated with two histidines and one glutamate. The new parameters were tested on a set of 21 different systems comprising 8 different peptidases, 5 DPP III orthologues, thermolysin, neprilysin, and aminopeptidase N, and the results are summarized in the second part of the article.

A comprehensive study of the complexation of alkali metal cations by lower rim calix[4]arene amide derivatives.

The complexation of alkali metal cations by lower rim N,N-dihexylacetamide (L1) and newly synthesized N-hexyl-N-methylacetamide (L2) calix[4]arene tertiary-amide derivatives was thoroughly studied at 25 °C in acetonitrile (MeCN), benzonitrile (PhCN), and methanol (MeOH) by means of direct and competitive microcalorimetric titrations, and UV and 1H NMR spectroscopies. In addition, by measuring the ligands' solubilities, the solution (transfer) Gibbs energies of the ligands and their alkali metal complexes were obtained. The inclusion of solvent molecules in the free and complexed calixarene hydrophobic cavities was also investigated. Computational (classical molecular dynamics) investigations of the studied systems were also carried out. The obtained results were compared with those previously obtained by studying the complexation ability of an N-hexylacetamidecalix[4]arene secondary-amide derivative (L3). The stability constants of 1 : 1 complexes were determined in all solvents used (the values obtained by different methods being in excellent agreement), as were the corresponding complexation enthalpies and entropies. Almost all of the examined reactions were enthalpically controlled. The most striking exceptions were reactions of Li+ with both ligands in methanol, for which the entropic contribution to the reaction Gibbs energy was substantial due the entropically favourable desolvation of the smallest lithium cation. The thermodynamic stabilities of the complexes were quite solvent dependent (the stability decreased in the solvent order: MeCN > PhCN ≫ MeOH), which could be accounted for by considering the differences in the solvation of the ligand and free and complexed alkali metal cations in the solvents used. Comparison of the stability constants of the ligand L1 and L2 complexes clearly revealed that the higher electron-donating ability of the hexyl with respect to the methyl group is of considerable importance in determining the equilibria of the complexation reactions. Additionally, the quite strong influence of intramolecular hydrogen bond formation in compound L3 (not present in ligands L1 and L2) and that of the inclusion of solvent molecules in the calixarene hydrophobic cone were shown to be of great importance in determining the thermodynamic stability of the calixarene-cation complexes. The experimental results were fully supported by those obtained by MD simulations.

Halogen and Hydrogen Bonding between (N-Halogeno)-succinimides and Pyridine Derivatives in Solution, the Solid State and In Silico.

A study of strong halogen bonding within three series of halogen-bonded complexes, derived from seven para-substituted pyridine derivatives and three N-halosuccinimides (iodo, bromo and chloro), has been undertaken with the aid of single-crystal diffraction, solution complexation and computational methods. The halogen bond was compared with the hydrogen bond in an equivalent series based on succinimide. The halogen-bond energies are in the range -60 to -20 kJ mol-1 and change regularly with pyridine basicity and the Lewis acidity of the halogen. The halogen-bond energies correlate linearly with the product of charges on the contact atoms, which indicates a predominantly electrostatic interaction. The binding enthalpies in solution are around 19 kJ mol-1 less negative due to solvation effects. The optimised geometries of the complexes in the gas phase are comparable to those of the solid-state structures, and the effects of the supramolecular surroundings in the latter are discussed. The bond energies for the hydrogen-bonded series are intermediate between the halogen-bond energies of iodine and bromine, although there are specific differences in the geometries of the halogen- and hydrogen-bonded complexes.

Small molecule probes finely differentiate between various ds- and ss-DNA and RNA by fluorescence, CD and NMR response.

Two small molecules showed intriguing properties of analytical multipurpose probes, whereby one chromophore gives different signal for many different DNA/RNA by application of several highly sensitive spectroscopic methods. Dyes revealed pronounced fluorescence ratiomeric differentiation between ds-AU-RNA, AT-DNA and GC-DNA in approximate order 10:8:1. Particularly interesting, dyes showed specific fluorimetric response for poly rA even at 10-fold excess of any other ss-RNA, and moreover such emission selectivity is preserved in multicomponent ss-RNA mixtures. The dyes also showed specific chiral recognition of poly rU in respect to the other ss-RNA by induced CD (ICD) pattern in visible range (400-500 nm), which was attributed to the dye-side-chain contribution to binding (confirmed by absence of any ICD band for reference compound lacking side-chain). Most intriguingly, minor difference in the side-chain attached to dye chromophore resulted in opposite sign of dye-ICD pattern, whereby differences in NMR NOESY contacts and proton chemical shifts between two dye/oligo rU complexes combined with MD simulations and CD calculations attributed observed bisignate ICD to the dimeric dye aggregate within oligo rU.

The effect of specific solvent-solute interactions on complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative.

Complexation of alkali-metal cations with calix[4]arene secondary-amide derivative, 5,11,17,23-tetra(tert-butyl)-25,26,27,28-tetra(N-hexylcarbamoylmethoxy)calix[4]arene (L), in benzonitrile (PhCN) and methanol (MeOH) was studied by means of microcalorimetry, UV and NMR spectroscopies, and in the solid state by X-ray crystallography. The inclusion of solvent molecules (including acetonitrile, MeCN) in the calixarene hydrophobic cavity was also investigated. The classical molecular dynamics (MD) simulations of the systems studied were carried out. By combining the results obtained using the mentioned experimental and computational techniques, an attempt was made to get an as detailed insight into the complexation reactions as possible. The thermodynamic parameters, that is, equilibrium constants, reaction Gibbs energies, enthalpies, and entropies, of the investigated processes were determined and discussed. The stability constants of the 1:1 (metal:ligand) complexes measured by different methods were in very good agreement. Solution Gibbs energies of the ligand and its complexes with Na(+) and K(+) in methanol and acetonitrile were determined. It was established that from the thermodynamic point of view, apart from cation solvation, the most important reason for the huge difference in the stability of these complexes in the two solvents lay in the fact that the transfer of complex species from MeOH to MeCN was quite favorable. That could be at least partly explained by a more exergonic inclusion of the solvent molecule in the complexed calixarene cone in MeCN as compared to MeOH, which was supported by MD simulations. Molecular and crystal structures of the lithium cation complex of L with the benzonitrile molecule bound in the hydrophobic calixarene cavity were determined by single-crystal X-ray diffraction. As far as we are aware, for the first time the alkali-metal cation was found to be coordinated by the solvent nitrile group in a calixarene adduct. According to the results of MD simulations, the probability of such orientation of the benzonitrile molecule included in the ligand cone was by far the largest in the case of LiL(+) complex. Because of the favorable PhCN-Li(+) interaction, L was proven to have the highest affinity toward the lithium ion in benzonitrile, which was not the case in the other solvents examined (in acetonitrile, sodium complex was the most stable, whereas in methanol, complexation of lithium was not even observed). That could serve as a remarkable example showing the importance of specific solvent-solute interactions in determining the equilibrium in solution.

An Integrated approach (thermodynamic, structural, and computational) to the study of complexation of alkali-metal cations by a lower-rim calix[4]arene amide derivative in acetonitrile.

The calix[4]arene secondary-amide derivative L was synthesized, and its complexation with alkali-metal cations in acetonitrile (MeCN) was studied by means of spectrophotometric, NMR, conductometric, and microcalorimetric titrations at 25 °C. The stability constants of the 1:1 (metal/ligand) complexes determined by different methods were in excellent agreement. For the complexation of M(+) (M = Li, Na, K) with L, both enthalpic and entropic contributions were favorable, with their values and mutual relations being quite strongly dependent on the cation. The enthalpic and overall stability was the largest in the case of the sodium complex. Molecular and crystal structures of free L, its methanol and MeCN solvates, the sodium complex, and its MeCN solvate were determined by single-crystal X-ray diffraction. The inclusion of a MeCN molecule in the calixarene hydrophobic cavity was observed both in solution and in the solid state. This specific interaction was found to be stronger in the case of metal complexes compared to the free ligand because of the better preorganization of the hydrophobic cone to accept the solvent molecule. Density functional theory calculations showed that the flattened cone conformation (C(2) point group) of L was generally more favorable than the square cone conformation (C(4) point group). In the complex with Na(+), L was in square cone conformation, whereas in its adduct with MeCN, the conformation was slightly distorted from the full symmetry. These conformations were in agreement with those observed in the solid state. The classical molecular dynamics simulations indicated that the MeCN molecule enters the L hydrophobic cavity of both the free ligand and its alkali-metal complexes. The inclusion of MeCN in the cone of free L was accompanied by the conformational change from C(2) to C(4) symmetry. As in solution studies, in the case of ML(+) complexes, an allosteric effect was observed: the ligand was already in the appropriate square cone conformation to bind the solvent molecule, allowing it to more easily and faster enter the calixarene cavity.

Interactions of multicationic bis(guanidiniocarbonylpyrrole) receptors with double-stranded nucleic acids: syntheses, binding studies, and atomic force microscopy imaging.

Compounds 1-3, composed of two guanidiniocarbonylpyrrole moieties linked by oligoamide bridges and differing in number and type of basic groups, were prepared. The sites and degree of protonation of 1-3 depend strongly on the pH value. The interactions of these compounds with several double-stranded (ds) DNA and dsRNA were investigated by means of UV/Vis and CD spectroscopy as well as isothermal titration microcalorimetry (ITC). These studies revealed that the binding of 1-3 to the polynucleotides is driven by three factors, the presence of aliphatic amino groups, the protonation state of the compounds, and the steric properties of the polynucleotide binding site, that is, the shape and structure of their grooves. The results obtained by all applied methods consistently indicated that receptors 1-3 bind to the minor groove of DNA, but, by contrast, to the major groove of RNA. Additionally, it was shown by atomic force microscopy (AFM) imaging that upon interaction of compound 2 with calf thymus (ct) DNA induced aggregation of the DNA occurs, leading to pronounced changes in its secondary structure.

Vanadium-induced formation of thiadiazole and thiazoline compounds. Mononuclear and dinuclear oxovanadium(v) complexes with open-chain and cyclized thiosemicarbazone ligands.

Reactions of the salicylaldehyde 4-phenylthiosemicarbazone (H(2)L) with selected vanadium(iv) and vanadium(v) precursors ([VO(acac)(2)], [VO(OAc)(2)], VOSO(4), [V(2)O(4)(acac)(2)]) were investigated under aerobic conditions in different alcohols (methanol, ethanol, propanol). In all examined cases mononuclear alkoxo vanadium(v) complexes [VOL(OR)] (1) (OR = OMe, OEt, OPr) were isolated as major products. On prolonged standing, mother liquids afforded dinuclear vanadium(v) complexes [V(2)O(3)(L(cycl))(2)(OR)(2)] (3) (OR = OMe, OEt, OPr), where L(cycl)(-) represents 1,3,4-thiadiazole ligand, formed by vanadium-induced oxidative cyclization of H(2)L. When [VO(acac)(2)] or [V(2)O(4)(acac)(2)] were used as precursors, in addition to products 1 and 3, a thiazoline derivative HL(acac)(cycl) (2) was isolated. This compound, formed by a reaction between acetylacetone and H(2)L, represented the second type of cyclic product. The products were characterized by IR and NMR spectroscopies, TG analysis, and in some cases by single-crystal X-ray diffraction. To the best of our knowledge, compounds [V(2)O(3)(L(cycl))(2)(OR)(2)] represent the first structurally characterized dinuclear vanadium(v) complexes with a thiadiazole moiety acting as a bridging ligand. Complexes 1 and 3, when dissolved in an appropriate alcohol, underwent substitution of the alkoxo ligand as confirmed by XRPD. The kinetics of reactions in methanolic solutions was qualitatively studied by UV-Vis and ESMS spectrometries. Under the experimental conditions applied, a relatively slow formation of the mononuclear complex [VOL(OMe)] and an even slower formation of the cyclic species 2 were observed, whereas the presence of dinuclear compound [V(2)O(3)(L(cycl))(2)(OMe)(2)] in the reaction mixture could not be detected.