Valinomycin Complex Research Articles

Crystal structures of valinomycin with potassium tetrachloroaurate and rubidium tetrachloroaurate with comparisons to other monovalent cation complexes

A total of 19 different crystal forms of complexes of valinomycin or its analogues with monovalent cations have been observed. The crystal structure determinations of valinomycin potassium tetrachloroaurate and valinomycin rubidium tetrachloroaurate are given here.Including this work complete structure determinations have now been published on 7 with 2 more soon to appear. Comparisons of these structural results suggest that the valinomycin complex opens at the D-valyl (lactyl) end and that contacts are possible between the complexed cation and other molecules. Such contacts may play an important part in membrane transport.

Solution conformations of valinomycin-divalent cation complexes.

The solution conformations of complexes of valinomycin with magnesium and strontium were investigated by circular dichroism, nuclear magnetic resonance and infrared techniques. The results were compared with our earlier results on lithium, calcium, manganese and barium complexes. All these cations, except lithium, form 2:1 ion sandwich and 1:1 carrier-cation complexes with valinomycin. The 1:1 complex has a conformation different from that of the valinomycin-potassium complex. Lithium forms only the 1:1 complex. Strontium and barium form a large number of 1:2 complexes with open conformations rapidly interconverting in solution in addition to the above 2:1 and 1:1 complexes. These observations are rationalized taking into account the ionic radii and coordination numbers of the cations and the conformational restraints of valinomycin molecules. It is suggested that cations with co-ordination numbers of about six (magnesium and calcium) form the 2:1 and 1:1 complexes whereas those with higher co-ordination numbers (strontium and barium) form 1:2 complexes also.

The molecular mechanics of valinomycin. II: Comparative studies of alkali ion binding

AbstractWe have carried out a series of molecular mechanics calculations on the alkali ion complexes of valinomycin. For the ions Na+, K+, Rb+, and Cs+ we have found three‐fold rotationally symmetric conformations as the lowest energy structures, while for Li+ a markedly asymmetric configuration is preferred. The relative free energies of the complexes show that Li+ is by far the poorest binding partner in solution, followed by Na+, which is in turn far poorer than any of the three larger ions. The binding selectivity derives from the slower variation of the complexation free energy with ionic size than the ionic solvation free energy, so that the ionophore is unable to compete with the solvent for the smaller ions. Our calculated strain energies suggest that valinomycin's failure to form complexes with the smaller ions in solution is due partially to the rigidity of the ionophore structure, which prevents the central cavity from contracting to accommodate them. Certain geometric criteria indicate that K+ provides the best fit to the binding site, although there is some inconsistency between the energetic and geometric criteria of binding ability.

The effect of the energy state of mitochondria on the kinetics of unidirectional cation fluxes

Unidirectional fluxes of triphenylmethylphosphonium and of Cs + as its valinomycin complex were studied using trace concentrations of the cations. The rate constants of influx and efflux were estimated mainly at 0 °C from the uptake kinetics in respiring mitochondria and the in/out ratios in the steady state. The efflux rate constants in the energized state were also measured after dilution of the mitochondrial suspension in the steady state, and in deenergized mitochondria from the efflux rates of cations after inhibition of respiration. It was found that the energy state of mitochondria had little effect on the rate constants of efflux, while the rate of influx was strongly stimulated by respiration. The former finding is not readily explained by the classical chemiosmotic theory, since a transmembrane potential, negative on the inside, formed on energization would be expected to strongly inhibit the efflux of cations. The data may be explained by a pump-and-leak model in which localized electrical fields in hydrophobic domains of the membrane are coupled to the pumping of hydrophobic cations against an electrochemical gradient, while leaks would effect efflux.

Circular dichroism and nuclear magnetic resonance studies on the complexation of valinomycin with calcium.

Complexation of valinomycin (VM) with the divalent cation Ca2+ in a lipophilic solvent, acetonitrile (CH3-CN), has been studied by using circular dichroism and proton and carbon-13 nuclear magnetic resonance (1H NMR and 13C NMR). From analyses of the spectral data, it is concluded that VM forms a 2:1 (peptide-ion-peptide) sandwich complex with Ca2+, at low concentration of VM. At moderate concentrations of the salt, in addition to the sandwich complex, an equimolar (1:1) complex different from those observed for potassium and sodium is also observed. At very large concentrations of the calcium salt, the data suggested a complex with a conformation similar to that of the free VM in polar solvents. Possible conformations for the sandwich and the equimolar VM-calcium complexes are proposed.

ChemInform Abstract: ALKALI CATION COMPLEXATION AND TRANSPORT PROPERTIES OF SYNTHETIC BICYCLIC DECAPEPTIDES: STRUCTURAL, THERMODYNAMIC, AND KINETIC ANALYSIS

AbstractMit Hilfe spektroskopischer Methoden (NMR und UV) sowie durch Mikrocalorimetrie wurde die Komplexierung von Alkalimetallkationen durch die bicyclischen Decapeptide S,S′‐ Bis‐[cyclo‐glycyl‐L‐hemicystyll‐glycyl‐glycyl‐L‐prolyl], S,S′‐Bis‐[cyclo‐glycyl‐L‐ hemicystyl‐glycyl‐glycyl‐D‐prc)lyl], S,S′‐Bis‐[cyclo‐glycyl‐L‐hemicystyl‐sarcosyl‐sarcosyl‐ ‐L‐prolyl‐] und S,S′‐Bis‐[cyclo‐glycyl‐L‐hemicystyl‐sarcosyl‐sarcosyl‐D‐prolyl] unter strukturellen, thermodynamischen und kinetischen Gesichtspunkten sowie die Eigenschaften der Peptide in bezug auf den Ionentransport in einem künstlichen Lipoid‐ Zweischichten‐System untersucht.

Alkali Cation Complexation and Transport Properties of Synthetic Bicyclic Decapeptides: Structural, Thermodynamic, and Kinetic Analysis

AbstractAlkali cation complexation and bilayer transport by the bicyclic decapeptides S,S′‐bis‐cyclo‐glycyl‐L‐hemicystyl‐glycyl‐glycyl‐L‐prolyl (1), S, S′‐bis‐cyclo‐glycyl‐L‐hemicystyl‐glycyl‐glycyl‐D‐prolyl (2), S, S′‐bis‐cyclo‐glycyl‐L‐ hemicystyl‐sarcosyl‐sarcosyl‐L‐prolyl (3), and S, S′‐bis‐cyclo‐glycyl‐L‐hemicystyl‐sarcosyl‐sarcosyl‐D‐prolyl (4) were analyzed according to structural, thermodynamic and kinetic criteria; valinomycin was used as a reference ionophoretic system.Structural analysis of peptide 3 with spectroscopic methods showed different conformational arrangements in the bicyclic system depending on its state of complexation. Circular dichroism indicated the presence of a multitude of conformations with differing helicities around the disulfide bridge in both free and complexed states.Thermodynamic analysis by microcalorimetry demonstrated a far lower cation selectivity among the synthetic peptides than displayed by valinomycin. Peptide 3 shows cation affinities of about two orders of magnitude higher than peptide 4, but still much lower than found for the complexes of valinomycin with K+ and Rb+. In contrast to the latter case, the complexation reactions of peptides 3 and 4 are driven by both enthalpy and entropy contributions. Neither peptide 1 and 2 nor the cyclic partial structures of all four peptides displayed significant cation complexation.A kinetic analysis of the K+‐complexation by peptide 3 based on the microcalorimetry experiments showed far lower rates of cation exchange for the synthetic peptide than those reported for valinomycin. Transport studies with peptide 3 using artificial lipid bilayer membranes gave negative results. The apparent lack of ionophoretic properties of these synthetic peptides despite their considerable ability to form complexes with cations is discussed in terms of structural parameters.

A thallium-205 nuclear magnetic resonance investigation of the thallium(I)-valinomycin complex

A thallium-205 nuclear magnetic resonance investigation of the thallium(I)-valinomycin complex

Transport of organic anions through the erythrocyte membrane as K+-valinomycin complexes.

K+, Rb+, or Cs+ complexes of valinomycin form ion pair complexes with picric acid and trinitrobenzenesulfonate (TNBS). The formation of a picrate-K+-valinomycin complex is supported by spectral evidence. These complexes have zero net charge and readily permeate the intact erythrocyte membrane. The K+-valinomycin complex has been used to convert the nonpenetrating TNBS into a penetrating covalent probe, making it as useful vectorial probe to measure accessible amino groups of proteins and phospholipids on both sites of the erythrocyte membrane. The enhanced transport of TNBS into the cell by valinomycin is dependent on external K+ in the medium. The entry of TNBS into the cell is manifested by an increased labeling of hemoglobin and membrane phosphatidylethanolamine (PE). Stilbeneisothiocyanatedisulfonate (SITS) and anilinonaphthalenesulfonate (ANS) inhibit both the basal and K+-valinomycin stimulated labeling of PE and hemoglobin by TNBS. The data suggest two independent effects of ANS and SITS, one mediated by an inhibition of the anion transport protein and another by the incorporation of these hydrobic anions into the cell membrane with an increase in negative charge on the membrane which leads to an inhibition of TNBS permeation into the cell by electrostatic repulsion.

Refinement of the solution conformation of valinomycin with the acid coupling constants from the 13C-nuclear-magnetic-resonance spectra.

The C′= O and Cα signals in the 13C nuclear magnetic resonance (NMR) spectra of valinomycin have been assigned and the vicinal 1H…13C coupling constants have been determined by double and triple heteronuclear resonance. In conjunction with the vicinal H-NCα-H and H-CαCβ-H proton-proton constants, the results led to unequivocal determination of the torsion angles φ and of the population distribution of the Cα-Cβ rotational states. The Φ torsion angles for the hydroxy acid residues were estimated from the vicinal 1H-CαC′-15N constants. The combined data permitted refinement of the conformational states of valinomycin in different solvents. For the KS+ complex of valinomycin the observed couplings are in complete accord with the conformations we had earlier proposed for solutions and that had also been established by X-ray analysis. In the 13C spectra of the valinomycin-Tl+ complex 13C…203,205Tl+ spin-spin couplings were observed for the l and d-valine carbonyls, unequivocal proof of the donor-acceptor interaction with the cation. In media of weak polarity (cyclohexane, chloroform) the conformation of the valinomycin molecule is similar to that of the K+ complex. In such a ‘bracelet’ structure formed by six fused β-turns of type II and II′, the amino acid carbonyls are axial with certain inclination towards the symmetry axis. On formation of a 1:1 complex with a cation the carbonyl orientation changes, now bending towards the center of the molecular cavity. In the ‘propeller’ conformation, predominant in solvents of medium polarity (for instance CCl4/(C2H3)2SO, 3/1) the three β-turns are of type II. The 1H and 13C chemical shifts are interpreted in terms of conformational changes in the valinomycin molecule, intermolecular and intramolecular hydrogen bonds and interaction with the metal cation.

ChemInform Abstract: RAMAN SPECTROSCOPY OF UNCOMPLEXED VALINOMYCIN. I. THE SOLID STATE

The membrane-active antibiotic valinomycin has become an important model compound for studying selective ion transport in biological and synthetic membranes. This paper reports results of the first complete Raman spectroscopic study of uncomplexed valinomycin in the solid state. Splittings in the ester and amide C=O stretch regions of valinomycin samples recrystallized from n-octane, CC14, CHC13, CH3(CH2)2CI, CH3COCH3, or CH3CN indicate a structure resembling that ob- tained by x-ray crystallography. However, valinomycin recrystallized from o-dichlorobenzene and p-dioxane exhibits a consid- erably different structure. Comparison is made with the Raman spectra of model compounds in order to facilitate the identifi- cation of valinomycin vibrations. These results are extended to valinomycin solutions in an adjoining publication. The antibiotic valinomycin (VM) produced by the bacte- ria Streptomyces fulvissimus is known to complex with alkali cations selectively2 in the order Rb+ > K+ > Cs+ > Na+ > Li+ and to facilitate the transport of alkali cations across mi- tochondrial membranes with the same ~electivity.~~ Similar results have been obtained in model membrane system^.^,^ Studies of valinomycin analogues2 emphasize the importance of structural factors in complex formation, induced ionic permeability, and antimicrobial activity. Valinomycin is a 12-membered macrocyclic depsipetide in which L-valine, L-lactic acid, D-valine, and D-hydroxyisovaleric acid (HIV) are alternately joined by amide and ester linkagesaS The primary structure of VM (Figure la) suggests how it can facilitate the transport of cations across otherwise impermeable lipid barriers. There are 12 polar C=O groups, some of which can form structurally stabilizing intramolecular hydrogen bonds with the NH groups of the valine subunits, while others are free to bind a cation at the waterllipid interface via ion- dipole interactions. The nonpolar isopropyl and methyl residues can shield the hydrophilic C=O coordinated cation to facili- tate its diffusion through the hydrophobic regions of membrane interiors. This structure for the K+-VM complex has been verified by x-ray ~rystallography~ ~~ and inferred from NMR

Raman spectroscopy of uncomplexed valinomycin. I. The solid state.

The membrane-active antibiotic valinomycin has become an important model compound for studying selective ion transport in biological and synthetic membranes. This paper reports results of the first complete Raman spectroscopic study of uncomplexed valinomycin in the solid state. Splittings in the ester and amide C=O stretch regions of valinomycin samples recrystallized from n-octane, CC14, CHC13, CH3(CH2)2CI, CH3COCH3, or CH3CN indicate a structure resembling that ob- tained by x-ray crystallography. However, valinomycin recrystallized from o-dichlorobenzene and p-dioxane exhibits a consid- erably different structure. Comparison is made with the Raman spectra of model compounds in order to facilitate the identifi- cation of valinomycin vibrations. These results are extended to valinomycin solutions in an adjoining publication. The antibiotic valinomycin (VM) produced by the bacte- ria Streptomyces fulvissimus is known to complex with alkali cations selectively2 in the order Rb+ > K+ > Cs+ > Na+ > Li+ and to facilitate the transport of alkali cations across mi- tochondrial membranes with the same ~electivity.~~ Similar results have been obtained in model membrane system^.^,^ Studies of valinomycin analogues2 emphasize the importance of structural factors in complex formation, induced ionic permeability, and antimicrobial activity. Valinomycin is a 12-membered macrocyclic depsipetide in which L-valine, L-lactic acid, D-valine, and D-hydroxyisovaleric acid (HIV) are alternately joined by amide and ester linkagesaS The primary structure of VM (Figure la) suggests how it can facilitate the transport of cations across otherwise impermeable lipid barriers. There are 12 polar C=O groups, some of which can form structurally stabilizing intramolecular hydrogen bonds with the NH groups of the valine subunits, while others are free to bind a cation at the waterllipid interface via ion- dipole interactions. The nonpolar isopropyl and methyl residues can shield the hydrophilic C=O coordinated cation to facili- tate its diffusion through the hydrophobic regions of membrane interiors. This structure for the K+-VM complex has been verified by x-ray ~rystallography~ ~~ and inferred from NMR

Facilitated transport of di- and trinitrophenolate ions across lipid membranes by valinomycin and nonactin

The conductance of black lipid membranes in the presence of 2,4,6-trinitrophenol (or 2,4-dinitrophenol) is considerably enhanced, if the cation carriers valinomycin, enniatin B or nonactin are added. The effect is, however, largely independent of the cation concentration and is identical for the cations Li +, Na + and Ba 2+. This finding, as well as the sign and magnitude of the diffusion potential in the presence of a gradient of picrate are consistent with the assumption that the transport of picrate anions is facilitated by the above-mentioned macrocyclic compounds, but that cations are not directly involved. A model is suggested which, based on the generation of mobile defect structures by the incorporation of large molecules, allows one to explain facilitated transport without the assumption of stable chemical bonds between a carrier and its transported substrate. If K + is present in the aqueous phase, the conductance is largely determined by the permeation of the cation complexes of valinomycin and nonactin. The conductance is, however, increased by adsorption of picrate anions to the membrane surface. The negative surface potential generated by the adsorption layer seems to be responsible for the saturation of the conductance at high picrate concentrations in the absence of valinomycin and nonactin.

Conformational studies of peptide cyclo-(D-Val-L-Pro-L-Val-D-Pro]3, a cation-binding analogue of valinomycin.

The solution conformation of cyclo-[D-Val-L-Pro-L-Val-D-Pro]3 (PV) and its alkali-metal ion complexes was investigated by proton nuclear magnetic resonance spectroscopy. It is concluded that the cation complexes of PV have S6 symmetry and are essentially isostructural with the K complex of valinomycin. In contrast to valinomycin, the Li- and Na-PV complexes are stable in methanol and have dissociation rate constants that are several orders of magnitude slower than the corresponding valinomycin complexes. Also in contrast to valinomycin, free PV exists in two different conformational states which interconvert at very slow rates (less than 1 s-1). One of these conformers has S6 symmetry and is structurally similar to that of the cation complexes. The other species, which has lower symmetry than S6, is the more stable conformer. Depending upon concentration and solvent polarity, the latter represents between 50 and 75% of the total mixture. It is proposed that PV may have a higher affinity for cations than valinomycin because of its higher potential energy in the uncomplexed state.

Nuclear magnetic resonance studies of the interactions of anions and solvent with cation complexes of valinomycin

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNuclear magnetic resonance studies of the interactions of anions and solvent with cation complexes of valinomycinDonald G. Davis and Daniel C. TostesonCite this: Biochemistry 1975, 14, 18, 3962–3969Publication Date (Print):September 1, 1975Publication History Published online1 May 2002Published inissue 1 September 1975https://doi.org/10.1021/bi00689a006RIGHTS & PERMISSIONSArticle Views55Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (915 KB) Get e-Alerts Get e-Alerts

Ammonium ion proton magnetic resonance probe of cation-binding, cyclic antibiotics

Proton magnetic resonance (PMR) spectra of NH 4 + ions bound to the cyclic antibiotics valinomycin and nonactin can be analyzed to give, unambiguously, information about the rotational correlation times, τ R , the Stokes' radii, r S , and the 14 N quadrupolar coupling constants, e 2 qQ/h, for the different complexes. For the NH 4 + -valinomycin complex: τ R = 3.2 × 10 −11 sec; r S = 4 × 10 −8 cm and e 2 qQ/h = 1.2MHz. For nonactin: τ R = 1.3 × 10 −10 sec; r S = 6 × 10 −8 cm and e 2 qQ/h = 0. It is also found that the proton chemical shift of the ion is 0.6 ppm to higher field when it is complexed to valinomycin as compared to nonactin.

マクロライド系抗生物質の構造と機能

Macrocyclic antibiotics can bind alkali metal ions forming 1: 1 complexes, and act as cation-carriers (ionophores) passing through biological and artificial membranes. Molecular structures in crystals and conformational states in solutions are described for valinomycin and nactins, both in free and complexed states. Valinomycin molecule (oval shaped) possesses an approximate symmetry of 1 and six intramolecular H-bonds. On complexation, two H-bonds of 13-membered-ring are disrupted and new ones are formed to complete complex molecule of pseudo C3 symmetry with minor conformational change. In polar solvent, only three H-bonds are observed for K+-valinomycin complex, indicating that the molecule is widely opened to release K+ as ion-pump. In crystals, molecular shape of nonactin (‘torus’, C2 and an approximate S4 symmetry, less stable conformation) is markedly different from that of tetranactin (‘propeller’, C2 symmetry, stable), but they exhibit similar IR and NMR spectra in solutions which indicate molecular symmetry 4. Interconversion of the conformation of free and complexed nactins may be readily achieved by intramolecular motion. Energy differences in intra-ligand-steric-interaction among the complexes of nactins with alkali metal ions are rather small in comparison with those of ion-dipole interactions and hydration energies of cations.

Stability of sodium and potassium complexes of valinomycin

Stability constants of sodium and potassium complexes of valinomycin in some alcohols and water—organic solvent mixtures have been determined by titration, using circular dichroism to monitor complex formation. Constants range from 10 1 to 10 6 M −1. Stability of the potassium and sodium complexes increases with decreasing dielectric constant, but the ratio of the constants remains about 10 3–10 4. As others have shown, a similar selectivity for K + is observed in a number of other types of measurements involving valinomycin. These include the permeability and conductance ratios which characterize the selectivity of cation transport through membranes and the ratio of salt extraction equilibrium constants. On the basis of data presented here, and elsewhere, it is suggested that conformational constraints within the depsipeptide part of the complexes aid ion selectivity and that differences in cation solvation and carbonyl ligand binding energies make an important, roughly equal, contribution.

Relation between structure and properties of cyclodepsipeptides of valinomycin series

1. Employing the optical rotation dispersion, IR, and NMR spectroscopy methods, a study was made of the conformation states of some valinomycin analogs with modified side chains, and also of their K+ complexes. 2. A change in the side chains of valinomycin affects the relative stability of its conformation forms, but does not lead to the appearance of new forms. 3. In the “propeller” conformation the L-valine isopropyl groups shield the intramolecular H bonds from the action of the solvent. 4. Replacements of the valine residues by alanine moieties in the K+ complex of valinomycin are accompanied by an enhancement of the reaction of the solvent with the central ion. Such “unilateral” solvation leads to additional distortion of the symmetry of the system of chromophore groups in the complexes. The complexes of the analogs, obtained by the replacements L-Val→ L-Ala and D-Val→-D-Ala, have opposite chiralities of the depsipeptide chains.

The dissociation-rate dependent electrochemical reduction of valinomycin complexes of monovalent ions

Abstract The polarographic reduction of valinomycin complexes of alkali metal and thallium (I) ions takes place via dissociation of the complex while the free metal ions are reduced. The stability constants determined from the half-wave potentials and the dissociation-rate constants determined from the polarographic (limiting currents show a distinct ion-specificity. The values for the thallium (I) complex lie outside the sequence based on crystallographic ionic radii.