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PubMed1998

Thermodynamics of ligand binding and catalysis in human liver medium-chain acyl-CoA dehydrogenase: comparative studies involving normal and 3'-dephosphorylated C8-CoAs and wild-type and Asn191 --> Ala (N191A) mutant enzymes.

Following our demonstration that the terminal 3'-phosphate group of acyl-CoA substrates (which is confined to the exterior of the protein structure, and is fully exposed to the outside solvent environment) exhibits a functional role in the recombinant human liver medium-chain acyl-CoA dehydrogenase (MCAD)-catalyzed reaction [Peterson, K. L., and Srivastava, D. K. (1997) Biochem. J. 325, 751-760], we became interested in delineating its thermodynamic contribution in stabilizing the "ground" and "transition" state structures during enzyme catalysis. Since the 3'-phosphate group of the coenzyme A thiolester has the potential to form a hydrogen bond with the side chain group of Asn-191, these studies were performed utilizing both normal and 3'-dephosphorylated forms of octanoyl-CoA and octenoyl-CoA (cumulatively referred to as C8-CoA) as the physiological substrate and product of the enzyme, respectively, as well as utilizing wild-type and Asn191 --> Ala (N191A) site-specific mutant enzymes. The experimental data revealed that the enthalpic contribution of the 3'-phosphate group was similar in both ground and transition states, and was primarily derived from the London-van der Waals interactions (between the 3'-phosphate group of C8-CoA and the surrounding protein moiety), rather than from the potential hydrogen bonding. The temperature dependence of DeltaH degrees for the binding of octenoyl-CoA and 3'-dephosphooctenoyl-CoA revealed that the deletion of the 3'-phosphate group from octenoyl-CoA increased the magnitude of the heat capacity changes (DeltaCp degrees) from -0.53 to -0.59 kcal mol-1 K-1. Although the latter effect could be attributed to an increase in the relative hydrophobicity of the ligand, the experimentally observed DeltaCp degrees's (for either of the ligands) could not be predicted on the basis of the changes in the solvent-accessible surface areas of the enzyme and ligand species. These coupled with the fact that the DeltaCp degrees for the binding of octenoyl-CoA to pig kidney MCAD (which is believed to be structurally identical to human liver MCAD) is only -0.37 kcal mol-1 K-1 [Srivastava, D. K., Wang, S., and Peterson, K. L. (1997) Biochemistry 36, 6359-6366] prompt us to question the reliability of predicting the DeltaCp degrees values of the enzyme-ligand complexes from their X-ray crystallographic data. Arguments are presented that certain intrinisic limitations of the crystallographic data preclude kinetic and thermodynamic predictions about the enzyme-ligand complexes and enzyme catalysis.

Acyl Coenzyme A↗

PubMed1999

Thermodynamic analysis of alpha-spectrin SH3 and two of its circular permutants with different loop lengths: discerning the reasons for rapid folding in proteins.

The temperature dependences of the unfolding-refolding reaction of a shorter version of the alpha-spectrin SH3 domain (PWT) used as a reference and of two circular permutants (with different poly-Gly loop lengths at the newly created fused loop) have been measured by differential scanning microcalorimetry and stopped-flow kinetics, to characterize the thermodynamic nature of the transition and native states. Differential scanning calorimetry results show that all these species do not belong to the same temperature dependency of heat effect. The family of the N47-D48s circular permutant (with 0-6 Gly inserted at the fused-loop) shows a higher enthalpy as happens with the PWT domain. The wild type (WT) and the S19-P20s permutant family have a more similar behavior although the second is far less stable. The crystallographic structure of the PWT shows a hairpin formation in the region corresponding to the unstructured N-terminus tail of the WT, explaining the enthalpic difference. There is a very good correlation between the calorimetric changes and the structural differences between the WT, PWT, and two circular permutants that suggests that their unfolded state cannot be too different. Elongation of the fused loop in the two permutants, taking as a reference the protein with one inserted Gly, results in a small Gibbs energy change of entropic origin as theoretically expected. Eyring plots of the unfolding and refolding semireactions show different behaviors for PWT, S19-P20s, and N47-D48s in agreement with previous studies indicating that they have different transition states. The SH3 transition state is relatively close to the native state with regard to changes in heat capacity and entropy, indicating a high degree of compactness and order. Regarding the differences in thermodynamic parameters, it seems that rapid folding could be achieved in proteins by decreasing the entropic barrier.

Amino Acid Sequence↗

PubMed1999

Thermodynamic and kinetic studies on carbon-cobalt bond homolysis by ribonucleoside triphosphate reductase: the importance of entropy in catalysis.

In the catalytic mechanism of nucleotide reduction, ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii catalyzes the homolytic cleavage of the carbon-cobalt bond of adenosylcobalamin (AdoCbl) at a rate approximately 10(11)-fold faster than the uncatalyzed reaction. Model systems have suggested hypotheses for the thermodynamic basis of this reaction, but relevant measurements of the enzymatic reaction have been lacking. To address this question in a system for which the microscopic rate constants can be measured as a function of temperature, we examined the RTPR-catalyzed exchange reaction. RTPR, in the presence of allosteric effector dGTP and in the absence of substrate, catalyzes carbon-cobalt bond homolysis and formation of a thiyl radical from an active-site cysteine in a concerted fashion [Licht, S., Booker, S. , Stubbe, J. (1999) Biochemistry 38, 1221-1233]. Both the kinetics of cob(II)alamin formation and the amounts of cob(II)alamin formed have been studied as a function of AdoCbl concentration and temperature. Analysis of these data has allowed calculation of a DeltaH of 20 kcal/mol, a DeltaS of 70 cal mol-1 K-1, a DeltaH of 46 kcal/mol, and a DeltaS of 96 cal mol-1 K-1 for carbon-cobalt bond homolysis/thiyl radical formation. The results further show that the enzyme perturbs the equilibrium between the reactant (AdoCbl-bound) state and the product (cob(II)alamin/5'-deoxyadenosine (5'-dA)/thiyl radical state, making them approximately equal in energy. The thermodynamic perturbation, in addition to transition-state stabilization, is required for the large rate acceleration observed. Entropic, rather than enthalpic, factors make the largest contribution in both cases.

Allosteric Regulation↗

PubMed1999

The thermodynamics of polyamide-DNA recognition: hairpin polyamide binding in the minor groove of duplex DNA.

Crescent-shaped synthetic ligands containing aromatic amino acids have been designed for specific recognition of predetermined DNA sequences in the minor groove of DNA. Simple rules have been developed that relate the side-by-side pairings of Imidazole (Im) and Pyrrole (Py) amino acids to their predicted target DNA sequences. We report here thermodynamic characterization of the DNA-binding properties of the six-ring hairpin polyamide, ImImPy-gamma-PyPyPy-beta-Dp (where gamma = gamma-aminobutyric acid, beta = beta-alanine, and Dp = dimethylaminopropylamide). Our data reveal that, at 20 degrees C, this ligand binds with a relatively modest 1.8-fold preference for the designated match site, 5'-TGGTA-3', over the single base pair mismatch site, 5'-TGTTA-3'. By contrast, we find that the ligand exhibits a 102-fold greater affinity for its designated match site relative to the double base pair mismatch site, 5'-TATTA-3'. These results demonstrate that the energetic cost of binding to a double mismatch site is not necessarily equal to twice the energetic cost of binding to a single mismatch site. Our calorimetrically measured binding enthalpies and calculated entropy data at 20 degrees C reveal the ligand sequence specificity to be enthalpic in origin. We have compared the DNA-binding properties of ImImPy-gamma-PyPyPy-beta-Dp with the hairpin polyamide, ImPyPy-gamma-PyPyPy-beta-Dp (an Im --> Py "mutant"). Our data reveal that both ligands exhibit high affinities for their designated match sites, consistent with the Dervan pairing rules. Our data also reveal that, relative to their corresponding single mismatch sites, ImImPy-gamma-PyPyPy-beta-Dp is less selective than ImPyPy-gamma-PyPyPy-beta-Dp for its designated match site. This result suggests, at least in this case, that enhanced binding affinity can be accompanied by some loss in sequence specificity. Such systematic comparative studies allow us to begin to establish the thermodynamic database required for the rational design of synthetic polyamides with predictable DNA-binding affinities and specificities.

Base Pair Mismatch↗

PubMed1999

A thermodynamic comparison of mesophilic and thermophilic ribonucleases H.

The mechanisms by which thermophilic proteins attain their increased thermostability remain unclear, as usually the sequence and structure of these proteins are very similar to those of their mesophilic homologues. To gain insight into the basis of thermostability, we have determined protein stability curves describing the temperature dependence of the free energy of unfolding for two ribonucleases H, one from the mesophile Escherichia coli and one from the thermophile Thermus thermophilus. The circular dichroism signal was monitored as a function of temperature and guanidinium chloride concentration, and the resulting free energies of unfolding were fit to the Gibbs-Helmholtz equation to obtain a set of thermodynamic parameters for these proteins. Although the maximal stabilities for these proteins occur at similar temperatures, the heat capacity of unfolding for T. thermophilus RNase H is lower, resulting in a smaller temperature dependence of the free energy of unfolding and therefore a higher thermal melting temperature. In addition, the stabilities of these proteins are similar at the optimal growth temperatures for their respective organisms, suggesting that a balance of thermodynamic stability and flexibility is important for function.

Amino Acid Sequence↗

PubMed1999

Kinetics and thermodynamics of dimer formation and dissociation for a recombinant humanized monoclonal antibody to vascular endothelial growth factor.

The recombinant humanized antibody (rhuMAb) VEGF has a high affinity for vascular endothelial growth factor and is currently being evaluated in clinical trials as a cancer therapeutic. Under acidic pH and low ionic strength conditions, the antibody was predominantly present as monomer. Under physiological conditions, the appearance of significant amounts of a noncovalent, reversible dimer were observed by size-exclusion chromatography. The kinetics and thermodynamics of the reversible self-association for rhuMAb VEGF monomer were investigated as a function of pH, temperature, and ionic strength by size-exclusion chromatography using the concentration jump method. The rate constant for dimer formation ranged 23-112 M(-)(1) min(-)(1) under the conditions studied, values that are significantly lower than those reported in the literature for other proteins that self-associate. The rate constant for dissociation ranged 0.0039-0.021 min(-)(1). Gibbs' free energies, enthalpies, entropies, and activation energies were determined and revealed that dimer formation is optimal at pH 7.5-8.0, which may be reflective of charge shielding occurring near the pI of the protein. There was a negative change in entropy for dissociation (values from -18.1 to -12.8 cal/mol K). In the presence of D(2)O or 1 M NaCl, dimerization was enhanced. The results of the kinetic and thermodynamic analysis of this study indicate that rhuMAb VEGF dimerization occurs primarily through hydrophobic interactions.

Animals↗

PubMed1999

Triplex formation of chemically modified homopyrimidine oligonucleotides: thermodynamic and kinetic studies.

We have investigated effects of chemical modifications of a third strand on the thermodynamic and kinetic properties of the triplex formation between a 23-bp duplex and each of four kinds of 15-mer chemically modified third strands using isothermal titration calorimetry and interaction analysis system. The chemical modifications of the third strand included one base modification, with replacement of thymine by uracil; two sugar moiety modifications, RNA and 2'-O-methyl-RNA; and one phosphate backbone modification, with replacement of phosphodiester by phosphorothioate backbone. The thermodynamic and kinetic parameters obtained were similar in magnitude at room temperature for the triplex formation with the base-modified and the sugar-modified third strands. By contrast, binding constant for the triplex formation with the third strand containing phosphorothioate backbone was much smaller by a factor of 10 than that for the other triplex formations. Kinetic analyses have also demonstrated that the third strand containing phosphorothioate backbone was much slower in the association step and much faster in the dissociation step than the other third strands, which resulted in the much smaller binding constant. The reason for the instability of the triplex with the third strand containing phosphorothioate backbone will be discussed. We conclude that, at least in the triplex formation with the chemically modified third strands studied in the present work, the modification of phosphate backbone of the third strand produces more significant effect on the triplex formation than the modifications of base and sugar moiety.

Base Sequence↗

PubMed1999

Expression, folding, and thermodynamic properties of the bovine oxytocin-neurophysin precursor: relationships to the intermolecular oxytocin-neurophysin complex.

Earlier thermodynamic studies of the intermolecular interactions between mature oxytocin and neurophysin, and of the effects of these interactions on neurophysin folding, raised questions about the intramolecular interactions of oxytocin with neurophysin within their common precursor. To address this issue, the disulfide-rich precursor of oxytocin-associated bovine neurophysin was expressed in Escherichia coli and folded in vitro to yield milligram quantities of purified protein; evidence of significant impediments to yield resulting from damage to Cys residues is presented. The inefficiency associated with the refolding of reduced mature neurophysin in the presence of oxytocin was found not to be alleviated in the precursor. Consistent with this, the effects of pH on the spectroscopic properties of the precursor and on the relative stabilities of the precursor and mature neurophysin to guanidine denaturation indicated that noncovalent intramolecular bonding between oxytocin and neurophysin in the precursor had only a small thermodynamic advantage over the corresponding bonding in the intermolecular complex. Loss of the principal interactions between hormone and protein, and of the enhanced stability of the precursor relative to that of the mature unliganded protein, occurred reversibly upon increasing the pH, with a midpoint at pH 10. Correlation of these results with evidence from NMR studies of structural differences between the precursor and the intermolecular complex, which persist beyond the pH 10 transition, suggests that the covalent attachment of the hormone in the precursor necessitates a conformational change in its neurophysin segment and leads to properties of the system that are distinct from those of either the liganded or unliganded mature protein.

Animals↗

PubMed2000

Unfolding thermodynamics of the tetrameric chaperone, SecB.

SecB is a cytosolic tetrameric chaperone in Escherichia coli, which maintains polypeptides, destined for export in a translocation competent state. The thermodynamics of unfolding of SecB was studied as a function of protein concentration, by using high sensitivity-differential scanning calorimetry and spectroscopic methods. The thermal unfolding of tetrameric SecB is reversible and can be well described as a two-state transition in which the folded tetramer is converted directly to unfolded monomers. Increasing the pH decreases the stability of the tetramer significantly, the T(m) changing from 341.3 K at pH 6.5 to 332.6 K at pH 9.5. The value of DeltaC(p) obtained from measurements of DeltaH(m) as a function of T(m) was 10.7 +/- 0.7 kcal mol(-1) K(-1). The value of DeltaC(p) is among the highest measured for a multimeric protein. At 298 K, pH 7.4, the DeltaG degrees (u) for the SecB tetramer is 27.9 +/- 2 kcal mol(-1). Denaturant-mediated unfolding of SecB was found to be irreversible. The reactivity of the four solvent-exposed free thiols in tetrameric SecB is salt dependent. The kinetics of reactivity suggests that these four cysteines are in close proximity to each other and that these residues on each monomer are in chemically identical environments. The thermodynamic data suggest that SecB is a stable, well-folded, and tightly packed tetramer and that substrate binding occurs at a surface site rather than at an interior cavity.

Bacterial Proteins↗

PubMedDate not supplied

Thermodynamic measurements and predictions of the adsorption of short-chain peptides on nanothin polymer films.

This contribution describes experimental measurements of submolecular-level interaction energies involved in the process of peptide adsorption on polymer films. The objective of this study was to use surface plasmon resonance (SPR) spectroscopy to measure the Gibbs energy change on adsorption (DeltaG(ad)) for pairs of various homopeptides on highly uniform, nanothin polymer films and to use these data, along with the principle of additivity, to predict DeltaG(ad) for homologous homopeptides, as well as for a mixed-residue peptide. By using a graft polymerization methodology, a nanothin poly(2-vinylpyridine) film was prepared and adsorption energies were measured first for a homologous series of tyrosine (Y) homopeptides on this film to determine submolecular-level interaction energies. By using SPR, adsorption isotherms were measured for YY and YYY peptides; analysis of these isotherms provided DeltaG(ad) data for a midchain tyrosine unit and a set of chain-end tyrosine units; values were -0.75 +/- 0.07 kcal/mol and -2.12 +/- 0.04 kcal/mol, respectively. Combining the thermodynamic contributions for adsorption of individual tyrosine units allowed a predictive estimate of -5.12 +/- 0.32 kcal/mol for the adsorption energy for YYYYYY; this estimate deviated by only 2.3% from its measured value of -5.24 +/- 0.06 kcal/mol. Similarly, adsorption energies were found for phenylalanine, glycine, and tyrosine-leucine peptides. Combining the thermodynamic contributions for adsorption of individual residue units allowed a predictive estimate of -3.24 +/- 0.38 kcal/mol for a pentapeptide, leucine enkephalin; this estimate deviated by only 3.0% from its measured value of -3.34 +/-0.11 kcal/mol.

Adsorption↗

PubMedDate not supplied

Carbohydrate polymers in amorphous states: an integrated thermodynamic and nanostructural investigation.

The effect of water on the structure and physical properties of amorphous polysaccharide matrices is investigated by combining a thermodynamic approach including pressure- and temperature-dependent dilatometry with a nanoscale analysis of the size of intermolecular voids using positron annihilation lifetime spectroscopy. Amorphous polysaccharides are of interest because of a number of unusual properties which are likely to be related to the extensive hydrogen bonding between the carbohydrate chains. Uptake of water by the carbohydrate matrices leads to a strong increase in the size of the holes between the polymer chains in both the glassy and rubbery states while at the same time leading to an increase in matrix free volume. Thermodynamic clustering theory indicates that, in low-moisture carbohydrate matrices, water molecules are closely associated with the carbohydrate chains. Based on these observations, we propose a novel model of plasticization of carbohydrate polymers by water in which the water dynamically disrupts chains the hydrogen bonding between the carbohydrates, leading to an expansion of the matrix originating at the nanolevel and increasing the number of degrees of freedom of the carbohydrate chains. Consequently, even in the glassy state, the uptake of water leads to increased rates of matrix relaxation and mobility of small permeants. In contrast, low-molecular weight sugars plasticize the carbohydrate matrix without appreciably changing the structure and density of the rubbery state, and their role as plasticizer is most likely related to a reduction of the number of molecular entanglements. The improved molecular packing in glassy matrices containing low molecular weight sugars leads to a higher matrix density, explaining, despite the lower glass transition temperature, the reduced mobility of small permeants in such matrices.

Carbohydrate Conformation↗

PubMedDate not supplied

Interactions of two amphiphilic penicillins with myoglobin in aqueous buffered solutions: a thermodynamic and spectroscopy study.

The interactions and complexation process of the amphiphilic penicillins sodium cloxacillin and sodium dicloxacillin with horse myoglobin in aqueous buffered solutions of pH 4.5 and 7.4 have been examined by equilibrium dialysis, zeta-potential, isothermal titration calorimetry (ITC) and UV-Vis absorbance techniques. A more opened structure of the protein molecules is detected as a consequence of the reduction of pH from 7.4 to 4.5. Binding isotherms and derived Hill coefficients reflect a cooperative binding behavior. Gibbs energies of binding per mole of drug were obtained from equilibrium dialysis data and compared with those derived from the zeta potential taking into account cooperativity. DeltaGads degrees values so obtained are large and negative at low concentrations where binding to the "high-energy" sites occurs and decreases with the drug concentration. The enthalpies of binding have been obtained from ITC and are small and exothermic so that the Gibbs energies of binding are dominated by large increases in entropy consistent with hydrophobic interactions. Other thermodynamic quantities of the binding mechanism, that is, entropy, DeltaSITCi, Gibbs energy, DeltaGITCi, the binding constant, KITCi, and the number of binding sites, ni, were also obtained, confirming the above results. From ITC data and following a theoretical model, the number of bound and free penicillin molecules was calculated, being higher at pH 4.5 than at pH 7.4. The binding of penicillin causes a conformational transition on protein structure as a consequence of the resulting intramolecular repulsion between the penicillin molecules bound to the protein. Thermodynamic quantites (the Gibbs energy of the transition in water, DeltaGw degrees , and in a hydrophobic environment, DeltaGhc degrees) of the denaturation process were calculated, indicating that at pH 4.5 some of the histidine residues are protonated, becoming accessible to solvent and giving rise to a more opened protein structure.

Animals↗

PubMedDate not supplied

Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpies of fusion and their application to estimates of enthalpies of sublimation and aqueous solubilities.

Comparative Molecular Field Analysis (CoMFA) has been used to develop three-dimensional quantitative structure-property relationship (3D-QSPR) models for the fusion enthalpy at the melting point (Delta(fus)H(m)(T(fus))) of a representative set of polychlorinated biphenyls (PCBs). Various alignment schemes, such as inertial, as is, atom fit, and field fit, were used in this study to evaluate the predictive capabilities of the models. The CoMFA models have also been derived using partial atomic charges calculated from the electrostatic potential (ESP) and Gasteiger-Marsili (GM) methods. The combination of atom fit alignment and GM charges yielded the greatest self-consistency (r(2) = 0.955) and internal predictive ability (r(cv)(2) = 0.783). This CoMFA model was used to predict Delta(fus)H(m)(T(fus)) of the entire set of 209 PCB congeners, including 193 PCB congeners for which experimental values are unavailable. The CoMFA-predicted values, combined with previous estimations of vaporization and sublimation enthalpies, were used to construct a thermodynamic cycle that validated the internal self-consistency of the predictions for these three thermodynamic properties. The CoMFA-predicted values of fusion enthalpy were also used to calculate aqueous solubilities of PCBs using Mobile Order and Disorder Theory. The agreement between calculated and experimental values of solubility at 298.15 K, characterized by a standard deviation of +/- 0.41 log units, demonstrates the utility of CoMFA-predicted values of fusion enthalpies to calculate aqueous solubilities of PCBs.

Environmental Pollutants↗

PubMed2001

Thermodynamic modeling of PCDD/Fs formation in thermal processes.

Three thermodynamic databases of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), derived using the Group Additivity approach and two computational molecular modeling methods, Modified Neglect of Diatomic Overlap (MNDO) and Parametrized Model 3 (PM3), respectively, combined with the Scientific Group Thermodata Europe (SGTE) database have been used to model the formation of PCDD/Fs in thermal processes, such as iron ore sintering process. The predictions using the three different databases are compared, and similar thermodynamic conditions of PCDD/Fs formation are found. The comparison of the calculated values with measured results obtained from industrial iron ore sinter plant indicates that the PCDDs and PCDFs found in practice are not in equilibrium with each other. While within each dioxin and furan homologue equilibrium between the isomers appears to be established in industrial processes, reactions between dioxins and furans seem to be kinetically inhibited. This view has been supported by assuming no reaction at all between PCDFs and PCDDs in the simulation. With this assumption, both PCDFs and PCDDs reached partial pressures between 600 and 800 K in the order of magnitude actually found in practice. Taking this restriction into account, the conditions for PCDD/Fs formation were calculated as a function of oxygen partial pressure; temperature; concentrations of carbon, hydrogen, and chlorine; and C/H ratio.

Benzofurans↗

PubMed2006

Experimental evidence for a lack of thermodynamic control on hydrogen concentrations during anaerobic degradation of chlorinated ethenes.

Hydrogen (H2) concentrations during reductive dechlorination of cis-dichloroethene (cDCE) and vinyl chloride (VC) were investigated with respectto the influence of parameters entering the Gibbs free energy expression of the reactions. A series of laboratory experiments was conducted employing a mixed, Dehalococcoides-containing enrichment culture capable of complete dechlorination of chlorinated ethenes. The objective was to investigate whether a constant energy gain controls H2 levels in dechlorinating systems, thereby evaluating the applicability of the partial equilibrium approach to microbial dechlorination at contaminated sites. Variations in the temperature between 10 and 30 degrees C did not affect the H2 concentration in a fashion that suggested thermodynamic control through a constant energy gain. In another set of experiments, H2 levels at constant ionic strength were independent of the chloride concentration between 10 and 110 mmol chloride per liter. These findings demonstrate that the partial equilibrium approach is not directly applicable to the interpretation of reductive degradation of chlorinated ethenes. We also present recalculated thermodynamic properties of aqueous chlorinated ethene species that allow for calculation of in-situ Gibbs free energy of dechlorination reactions at different temperatures.

Algorithms↗

PubMed2000

Plutonium(IV) sequestration: structural and thermodynamic evaluation of the extraordinarily stable cerium(IV) hydroxypyridinonate complexes.

Ligands containing the 1-methyl-3-hydroxy-2(1H)-pyridinone group (Me-3,2-HOPO) are powerful plutonium(IV) sequestering agents. The Ce(IV) complexes of bidentate and tetradentate HOPO ligands have been quantitatively studied as models for this sequestration. The complexes Ce(L1)4, Ce(L2)4, Ce(L3)2, and Ce(L4)2 (L1 = Me-3,2-HOPO; L2 = PR-Me-3,2-HOPO; L3 = 5LI-Me-3,2-HOPO; L4 = 5LIO-Me-3,2-HOPO) were prepared in THF solution from Ce(acac)4 and the corresponding ligand. The complex Ce(L4)2 was also prepared in aqueous solution by air oxidation of the Ce(III) complex [Ce(L4)2]-. Single-crystal X-ray diffraction analyses are reported for Ce(L1)(4)x2CHCl3 [P1 (no. 2), Z = 2, a = 9.2604(2) A, b = 12.1992(2) A, c = 15.9400(2) A, alpha = 73.732(1) degrees, beta = 85.041(1) degrees, gamma = 74.454(1) degrees], Ce(L3)2x2CH3OH [P2(1)/c (no. 14), Z = 4, a = 11.7002(2) A, b = 23.0033(4) A, c = 15.7155(2) A, beta = 96.149(1) degrees], Ce(L4)(2).2CH3OH [P1 (no. 2), Z = 2, a = 11.4347(2) A, b = 13.8008(2) A, c = 15.2844(3) A, alpha = 101.554(1) degrees, beta = 105.691(1) degrees, gamma = 106.746(1) degrees], and Ce(L4)2x4H2O [P2(1)/c (no. 14), Z = 4, a = 11.8782(1) A, b = 22.6860(3) A, c = 15.2638(1) A, beta = 96.956(1) degrees]. A new criterion, the shape measure S, has been introduced to describe and compare the geometry of such complexes. It is defined as [formula: see text], where m is the number of edges, delta i is the observed dihedral angle along the ith edge of delta (angle between normals of adjacent faces), theta i is the same angle of the corresponding ideal polytopal shape theta, and min is the minimum of all possible values. For these complexes the shape measure shows that the coordination geometry is strongly influenced by small changes in the ligand backbone or solvent. Solution thermodynamic studies determined overall formation constants (log beta) for Ce(L2)4, Ce(L3)2, and Ce(L4)2 of 40.9, 41.9, and 41.6, respectively. A thermodynamic cycle has been used to calculate these values from the corresponding formation constants of Ce(III) complexes and standard electrode potentials. From the formation constants and from the protonation constants of the ligands, extraordinarily high pM values for Ce(IV) are generated by these tetradentate ligands (37.5 for Ce(L3)2 and 37.0 for Ce(L4)2). The corresponding constants for Pu(IV) are expected to be substantially the same.

Crystallography, X-Ray↗

PubMed2003

Toward optimized high-relaxivity MRI agents: the effect of ligand basicity on the thermodynamic stability of hexadentate hydroxypyridonate/catecholate gadolinium(III) complexes.

The thermodynamic stabilities of the Gd(III) complexes of five hexadentate ligands, which incorporate the 2,3-dihydroxyterephthalamide and 2,3-hydroxypyridonate chelating moieties, have been determined by potentiometric and spectrophotometric titration. The ligands were chosen to span a range of basicities while maintaining a similar tripodal structural motif, facilitating a study of the effect of ligand basicity on the thermodynamic stability of the Gd(III) complexes. The relative stability of the five complexes is found to be highly pH dependent, with the most acidic ligands forming the most stable complexes at low pH and more basic ligands forming more stable complexes at high pH. The most stable Gd(III) complex at a physiological pH of 7.4 is formed with a ligand of intermediate basicity and is of stability comparable to that of Gd(III) complexes that feature eight-coordinate amino-carboxylate ligands and are currently used as magnetic resonance imaging contrast agents in diagnostic medicine. A single-crystal X-ray structure of the intermediate compound 3-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester is described: This compound crystallizes in the triclinic space group P1 with a = 7.4801(3) A, b = 8.0671(3) A, c = 8.3457(4) A, alpha = 72.242(2) degrees, beta = 80.693(2) degrees, gamma = 69.943(3) degrees, V = 449.60(3) A(3), Z = 2, and R = 0.042.

Catechols↗

PubMed2006

Metal-binding thermodynamics of the histidine-rich sequence from the metal-transport protein IRT1 of Arabidopsis thaliana.

The widespread ZIP family of transmembrane metal-transporting proteins is characterized by a large intracellular loop that contains a histidine-rich sequence whose biological role is unknown. To provide a chemical basis for this role, we prepared and studied a peptide corresponding to this sequence from the first iron-regulated transporter (IRT1) of Arabidopsis thaliana, which transports Fe2+ as well as Mn2+, Co2+, Zn2+, and Cd2+. Isothermal titration calorimetry (ITC) measurements, which required novel experiments and data analysis, and supporting spectroscopic methods were used to quantify IRT1's metal-binding affinity and associated thermodynamics. The peptide, PHGHGHGHGP, binds metal ions with 1:1 stoichiometry and stabilities that are consistent with the Irving-Williams series. Comparison of the metal-binding thermodynamics of the peptide with those of trien provides new insight about enthalpic and entropic contributions to the stability of the metal-peptide complex. Although Fe2+ and other IRT1-transported metal ions do not bind very tightly, this His-rich sequence has a very high entropy-driven affinity for Fe3+, which may have biological significance.

Amino Acid Sequence↗