Interaction of metal ions with carboxylic and carboxamide groups in protein structures

An analysis of the geometry of metal binding by carboxylic and carboxamide groups in proteins is presented. Most of the ligands are from aspartic and glutamic acid side chains. Water molecules bound to carboxylate anions are known to interact with oxygen lone-pairs. However, metal ions are also found to approach the carboxylate group along the C-O direction. More metal ions are found to be along the syn than the anti lone-pair direction. This seems to be the result of the stability of the five-membered ring that is formed by the carboxylate anion hydrogen bonded to a ligand water molecule and the metal ion in the syn position. Ligand residues are usually from the helix, turn or regions with no regular secondary structure. Because of the steric interactions associated with bringing all the ligands around a metal center, a calcium ion can bind only near the ends of a helix; a metal, like zinc, with a low coordination number, can bind anywhere in the helix. Based on the analysis of the positions of water molecules in the metal coordination sphere, the sequence of the EF hand (a calcium-binding structure) is discussed.     

Unusual silver coordination by mono-carboxylate utilization of a poly-carboxylate anion, solid-state structures of silver-tetrachlorophthalate with phthalazine and amine ligands

Silver carboxylate coordination with the tetrachlorophthalate anion, in combination with neutral donor ligands, has been found to deviate from other known poly-carboxylate complexes. Both complexes reported here, bis-[tetrachlorophthalato-silver phthalazine] and bis-[ammino-tetrachlorophthato-silver di-ammino-silver], utilize mixed carboxylate bonding types for silver coordination. In the case of the phthalazine ligand, both chelating and monodentate carboxylates form the framework for the oligomeric structure. In the case of the ammine ligand, one carboxylate forms a monodentate connection to a silver-ammine group, while the other is simply involved with hydrogen bonding to lock in a [(Ag-NH₃)₂-Ag-NH₃] substructure with an adjacent tetrachlorophthalato-silver unit. Both structures exhibit supramolecular connections via hydrogen bonding and π-π interactions.     

Mechanism of zinc coordination by point-mutated structures of the distal CCHC binding motif of the HIV-1 NCp7 protein

The kinetics of Zn(2+) binding by two point-mutated forms of the HIV-1 NCp7 C-terminal zinc finger, each containing tridentate binding motif HCC [Ser49(35-50)NCp7] or CCC [Ala44(35-50)NCp7], has been studied by stopped-flow spectrofluorimetry. Both the formation and dissociation rate constants of the complexes between Zn(2+) and the two model peptides depend on pH. The results are interpreted on the basis of a multistep reaction model involving three Zn(2+) binding paths due to three deprotonated states of the coordinating motif, acting as monodentate, bidentate, and tridentate ligands. For Ser49(35-50)NCp7 around neutral pH, binding preferentially occurs via the deprotonated Cys36 in the bidentate state also involving His44. The binding rate constants for the monodentate and bidentate states are 1 x 10(6) and 3.9 x 10(7) M(-)(1) s(-)(1), respectively. For Ala44(35-50)NCp7, intermolecular Zn(2+) binding predominantly occurs via the deprotonated Cys36 in the monodentate state with a rate constant of 3.6 x 10(7) M(-)(1) s(-)(1). In both mutants, the final state of the Zn(2+) complex is reached by subsequent stepwise ligand deprotonation and intramolecular substitution of coordinated water molecules. The rate constants for the intermolecular binding paths of the bidentate and tridentate states of Ala44(35-50)NCp7 and of the tridentate state of Ser49(35-50)NCp7 are much smaller than expected according to electrostatic considerations. This is attributed to conformational constraints required to achieve proper metal coordination during folding. The dissociation of Zn(2+) from both peptides is again characterized by a multistep process and takes place fastest via the protonated Zn(2+)-bound bidentate and monodentate states, with rate constants of approximately 0.3 and approximately 10(3) s(-)(1), respectively, for Ser49(35-50)NCp7 and approximately 4 x 10(-)(3) and approximately 500 s(-)(1), respectively, for Ala44(35-50)NCp7.     

Effect of the synergistic anion on electron paramagnetic resonance spectra of iron-transferrin anion complexes is consistent with bidentate binding of the anion.

Continuous wave (cw) X-band EPR spectra at approximately 90 K were obtained for iron-transferrin-anion complexes with 18 anions. Each anion had a carboxylate group and at least one other polar moiety. As the second polar group was varied from hydroxyl to carbonyl to amine to carboxylate, the EPR spectra changed from a dominant signal at g' approximately 4.3 with a second smaller peak at g' approximately 9 to a broad signal with intensity between g' approximately 5 and 7. Computer simulation indicated that the changes in the EPR spectra were due to changes in the zero field splitting parameter ratio, E/D, from approximately 1/3 for carbonate anion to approximately 0.04 for malonate anion. Observation of iron-13C coupling in the electron spin echo envelope modulation (ESEEM) for iron transferrin [1-13C]pyruvate indicated that the carboxylate group was bound to the iron. It is proposed that all of the anions behave as bidentate ligands, with coordination to the iron through both the carboxylate and proximal groups, and the carboxyl group serves as a bridge between the iron and a positively charged group on the protein.     

Stereochemistry of guanidine-metal interactions: implications for L-arginine-metal interactions in protein structure and function

The geometries of 150 guanidine-metal ion interactions retrieved from crystal structures deposited in the Cambridge Structural Database have been analyzed. Metal ions exhibit a preference for anti coordination stereochemistry in the plane of the unprotonated guanidine group, usually in chelate complexes with a diguanidine moiety, but syn-oriented interactions are occasionally found for single guanidine-metal interactions. Three L-arginine-metal coordination interactions are found in metalloenzyme structures deposited in the Protein Data Bank: biotin synthase from E. coli, His-67 --> Arg human carbonic anhydrase I, and inactivated B. caldovelox arginase complexed with L-arginine. In these proteins, L-arginine-metal coordination adopts syn/out-of-plane and anti/in-plane coordination stereochemistry. The implications of these results for L-arginine-metal interactions in protein structure and function are discussed. Although such interactions are rare, this analysis serves as a useful reference point for the growing interest in enzymes containing L-arginine residues that function as general bases or metal ligands.     

The coordination chemistry of niobium and tantalum pentamethoxides: a general discussion

The coordination ability of about 40 potential monodentate and bidentate ligands with niobium and tantalum pentamethoxides has been investigated and is discussed.     

Studies on the aminopeptidase activity of rat cathepsin H.

Three synthetic substrates H-Arg-NH-Mec, Bz-Arg-NH-Mec and H-Cit-NH-Mec (Bz, Benzoyl; NH-Mec, 4-methylcoumaryl-7-amide; Cit, citrulline) were used to characterize specificity requirements for the P1-S1 interaction of cathepsin H from rat liver. From rapid equilibrium kinetic studies it was shown that Km, kcat and the specificity constants kcat/Km are quite similar for substrates with a free alpha-amino group. In contrast, a 25-fold decrease of kcat/Km was observed for the N-terminal-blocked substrate Bz-Arg-NH-Mec. The activation energies for H-Arg-NH-Mec and Bz-Arg-NH-Mec were determined to be 37 kJ/mol and 55 kJ/mol, respectively, and the incremental binding energy delta delta Gb of the charged alpha-amino group was estimated to -8.1 kJ/mol at pH 6.8. The shown preference of cathepsin H for the unblocked substrates H-Arg-NH-Mec and H-Cit-NH-Mec was further investigated by inspection of the pH dependence of kcat/Km. The curves of the two substrates with a charged alpha-amino group showed identical bell-shaped profiles which both exhibit pKa1 and pKa2 values of 5.5 and 7.4, respectively, at 30 degrees C. The residue with a pKa1 of 5.5 in the acid limb of the activity profile of H-Arg-NH-Mec was identified by its ionization enthalpy delta Hion = 21 kJ/mol as a beta-carboxylate or gamma-carboxylate of the enzyme, whereas the residue with a pKa2 of 7.4 was assigned to the free alpha-amino group of the substrate with a delta Hion of 59 kJ/mol. Bz-Arg-NH-Mec showed a different pH-activity profile with a pKa1 of 5.4 and a pKa2 of 6.6 at 30 degrees C. Cathepsin H exhibits no preference for a basic P1 side chain as has been shown by the similar kinetics of H-Arg-NH-Mec and the uncharged, isosteric substrate H-Cit-NH-Mec. In summary, specific interactions of an anionic cathepsin H active site residue with the charged alpha-amino group of substrates caused transition state stabilization which proves the enzyme to act preferentially as an aminopeptidase.     

Syntheses, crystal structures and biological relevance of glycolato and S-lactato molybdates

Glycolato and S-lactato complexes containing the dioxomolybdenum(VI) moiety have been synthesized for studies on the role of the alpha-hydroxycarboxylato anion in the iron molybdenum cofactor of nitrogenase. The ligands in these complexes, vis K2[MoO2(glyc)2].H2O (H2glyc=glycolic acid, C2H4O3) (1) and (Na2[MoO2(S-lact)2])3.13H2O (H2lact=lactic acid, C3H6O3) (2) chelate through their alpha-alkoxyl and alpha-carboxyl oxygen atoms. In contrast, octanuclear K6[(MoO2)8(glyc)6(Hglyc)2].10H2O (3) formed by the reduction of the glycolato complex (1), features three different ligand binding modes: (i) non-bridging and bridging bidentate coordination of alpha-alkoxyl and alpha-carboxyl groups, and (ii) bidentate bridging using alpha-carboxyl group, leaving the alpha-alkoxyl group free. The octanuclear skeleton shows strong metal-metal interactions. The coordination modes in (1) and (2) mimic that of homocitrate to the iron molybdenum cofactor (FeMo-co) of nitrogenase. The bidentate coordination of alpha-alkoxyl and alpha-carboxyl groups shows that bond of alpha-carboxyl group to Mo is less susceptible to the oxidation state of molybdenum compared with the Mo-alpha-alkoxyl bond. This is supported by the dinuclear coordination of alpha-carboxyl group with free alpha-alkoxyl group in glycolato molybdate(V) (3).     

Model for calcium binding to gamma-carboxyglutamic acid residues of proteins: crystal structure of calcium alpha-ethylmalonate

The crystal structure of a Ca2+ salt of alpha-ethylmalonic acid was determined from three-dimensional X-ray diffraction data. The dicarboxylate anion represents the functional side chain of gamma-carboxyglutamic acid (Gla) residues, which are implicated as essential calcium-binding ligands in a variety of proteins. The alpha-ethylmalonate ion chelates the Ca2+ ion in a bidentate manner that involves an O atom from each of the two malonate carboxylate groups. This type of binding arises from the constrained arrangement of carboxylate ligands in the malonate group and may be of significance to the calcium-binding properties of Gla-containing sites in proteins. The Ca2+-malonate chelation forms a six-membered ring, which is stabilized by interactions that are consistent with the preferred stereochemistries of both calcium-carboxylate and metal-malonate complexes. No other interactions are observed between Ca2+ ions and alpha-ethylmalonate ions that depend upon the malonate juxtaposition of two carboxylate groups. The potential for this type of binding distinguishes Gla residues from the monocarboxylate residues, aspartate and glutamate, and confers a novel calcium-chelation ability upon Gla-containing sites in proteins.     

Molecular Docking Study of Beta-Glucosidase with Cellobiose,Cellotetraose and Cellotetriose

Beta-glucosidase (3.2.1.21) plays an essential role in the removal of non-reducing terminal glucosyl residues from glycosides. Recently, beta-glucosidase has been of interest for biomass conversion that acts in synergy with two other enzymes, endoglucanase and exo-glucanase. However, there is not much information available on the catalytic interactions of beta-glucosidase with its substrates. Thus, this study reports on the binding modes between beta-glucosidase from glycoside hydrolase family 1 namely BglB with cellobiose, cellotetraose and cellotetriose via molecular docking simulation. From the results, the binding affinities of BglB-cellobiose, BglB-cellotetraose, and BglB-cellotetriose complexes were reported to be -6.2kJ/mol , -5.68 kJ/mol and -5.63 kJ/mol, respectively. The detail interactions were also been investigated that revealed the key residues involved in forming hydrogen bonds (h-bond) with the substrates. These findings may provide valuable insigths in designing beta-glucosidase with higher cellobiose-hydrolyzing efficiency.     

Preparation, characterisation and crystal structure of two zinc(II) benzoate complexes with pyridine-based ligands nicotinamide and methyl-3-pyridylcarbamate

Two benzoate complexes namely tetrakis(μ₂-benzoato-O,O^′)-bis(μ₂-benzoato-O,O)-bis(nicotinamide-N)-tri-zinc(II), [Zn₃(benz)₆(nia)₂] (I) and bis(benzoato-O)-bis(methyl-3-pyridylcarbamate-N)-zinc(II), [Zn(benz)₂(mpcm)₂] (II) (benz=benzoate anion, nia=nicotinamide, mpcm=methyl-3-pyridylcarbamate) were prepared and characterised by elemental analysis, IR spectroscopy, thermal analysis and X-ray structure determination. The structure of the complex I is centrosymmetric, formed by a linear array of three zinc atoms. The central zinc atom shows octahedral coordination and is bridged to each of the terminal zinc atoms by three benzoate anions. Two of them act as bidentate, one as monodentate ligand. By additional coordination of the nia ligand, the terminal Zn atoms adopt tetrahedral surrounding. The structure of complex II contains two crystallographically independent [Zn(benz)₂(mpcm)₂] molecules. In each molecule, the zinc atom is tetrahedrally coordinated by two monodentate benzoate and two methyl-3-pyridylcarbamate ligands. Intermolecular hydrogen bonds of the N-H?O type connect molecules in the structures of complexes I and II to form a two-dimensional network. The three different types of carboxylate binding found in the complexes were distinguished also by values of carboxylate stretching vibrations in FT-IR spectra as well as by thermal decomposition of the complexes in nitrogen.     

The redox couple of the cytochrome c cyanide complex: the contribution of heme iron ligation to the structural stability, chemical reactivity, and physiological behavior of horse cytochrome c

Contrary to most heme proteins, ferrous cytochrome c does not bind ligands such as cyanide and CO. In order to quantify this observation, the redox potential of the ferric/ferrous cytochrome c-cyanide redox couple was determined for the first time by cyclic voltammetry. Its E0' was -240 mV versus SHE, equivalent to -23.2 kJ/mol. The entropy of reaction for the reduction of the cyanide complex was also determined. From a thermodynamic cycle that included this new value for the cyt c cyanide complex E0', the binding constant of cyanide to the reduced protein was estimated to be 4.7 x 10(-3) L M(-1) or 13.4 kJ/mol (3.2 kcal/mol), which is 48.1 kJ/mol (11.5 kcal/mol) less favorable than the binding of cyanide to ferricytochrome c. For coordination of cyanide to ferrocytochrome c, the entropy change was earlier experimentally evaluated as 92.4 J mol(-1) K(-1) (22.1 e.u.) at 25 K, and the enthalpy change for the same net reaction was calculated to be 41.0 kJ/mol (9.8 kcal/mol). By taking these results into account, it was discovered that the major obstacle to cyanide coordination to ferrocytochrome c is enthalpic, due to the greater compactness of the reduced molecule or, alternatively, to a lower rate of conformational fluctuation caused by solvation, electrostatic, and structural factors. The biophysical consequences of the large difference in the stabilities of the closed crevice structures are discussed.     

Benzoate fermentation by the anaerobic bacterium Syntrophus aciditrophicus in the absence of hydrogen-using microorganisms.

The anaerobic bacterium Syntrophus aciditrophicus metabolized benzoate in pure culture in the absence of hydrogen-utilizing partners or terminal electron acceptors. The pure culture of S. aciditrophicus produced approximately 0.5 mol of cyclohexane carboxylate and 1.5 mol of acetate per mol of benzoate, while a coculture of S. aciditrophicus with the hydrogen-using methanogen Methanospirillum hungatei produced 3 mol of acetate and 0.75 mol of methane per mol of benzoate. The growth yield of the S. aciditrophicus pure culture was 6.9 g (dry weight) per mol of benzoate metabolized, whereas the growth yield of the S. aciditrophicus-M. hungatei coculture was 11.8 g (dry weight) per mol of benzoate. Cyclohexane carboxylate was metabolized by S. aciditrophicus only in a coculture with a hydrogen user and was not metabolized by S. aciditrophicus pure cultures. Cyclohex-1-ene carboxylate was incompletely degraded by S. aciditrophicus pure cultures until a free energy change (DeltaG') of -9.2 kJ/mol was reached (-4.7 kJ/mol for the hydrogen-producing reaction). Cyclohex-1-ene carboxylate, pimelate, and glutarate transiently accumulated at micromolar levels during growth of an S. aciditrophicus pure culture with benzoate. High hydrogen (10.1 kPa) and acetate (60 mM) levels inhibited benzoate metabolism by S. aciditrophicus pure cultures. These results suggest that benzoate fermentation by S. aciditrophicus in the absence of hydrogen users proceeds via a dismutation reaction in which the reducing equivalents produced during oxidation of one benzoate molecule to acetate and carbon dioxide are used to reduce another benzoate molecule to cyclohexane carboxylate, which is not metabolized further. Benzoate fermentation to acetate, CO(2), and cyclohexane carboxylate is thermodynamically favorable and can proceed at free energy values more positive than -20 kJ/mol, the postulated minimum free energy value for substrate metabolism.     

The role of amino acid residues in the active site of a midgut microvillar aminopeptidase from the beetle Tenebrio molitor

Aminopeptidases are major enzymes in the midgut microvillar membranes of most insects and are targets of insecticidal Bacillus thuringiensis crystal delta-endotoxins. Sequence analysis and substrate specificity studies showed that these enzymes resemble mammalian aminopeptidase N, although information on the organization of their active site is lacking. The effect of pH at different temperatures on the kinetic parameters of Tenebrio molitor (Coleoptera) larval aminopeptidase showed that enzyme catalysis depend on a deprotonated (pK 7.6; DeltaH degrees (ion), 7.6 kJ/mol) and a protonated (pK 8.2; DeltaH degrees (ion), 16.8 kJ/mol) group. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and diethylpyrocarbonate inactivate the enzyme by modifying a pK 5.8 carboxylate and a imidazole group, respectively, with a reaction order around 1. Tetranitromethane changes the K(m) of the enzyme without affecting its V(max) by modifying a phenol group. The presence of a competitive inhibitor decrease the inactivation reaction rates in all these cases. EDTA inactivation of the aminopeptidase is affected by pH and temperature suggesting the involvement in metal binding of at least one deprotonated imidazole group (pK 5.8, DeltaH degrees (ion), 20 kJ/mol). The data support the hypothesis that T. molitor aminopeptidase catalysis depends on a catalytic metal and on a carboxylate and a protonated imidazole group, whereas substrate binding relies in one phenol and one carboxylate groups. The insect aminopeptidase shares common features with mammalian aminopeptidase N, although differing in details of substrate binding and in residues directly involved in catalysis.     

Effect of carboxylate and Na ions on the tautomeric status of 9-methylguanine

Interactions of 9-methylguanine (m9Gua) with carboxylate ion of acetic acid (CH3COO-) and Na+ were studied by 1H NMR spectroscopy and ab initio quantum chemical calculations of the B3LYP/6-31++G(d,p) and B3LYP/6-311++G(d,p) levels of theory. Changes in the m9Gua 1H NMR spectrum in the presence of the equimolar amount of sodium acetate (NaAc), which in anhydrous DMSO dissociates to CH3COO- and Na+, were interpreted as a consequence of a complex formation of m9Gua in the amino-keto-N1H tautomeric form (m9GuaN1H) with carboxylate ions via two H-bonds involving amino and N1H-imino protons. Quantum chemical calculations of interactions of the m9GuaN1H ground-state tautomer and the m9GuaN3H high energy one with relative energy 20.01 kcal/mol show that the ground state tautomer forms the ground-state complex CH3COO-:mgGuaN1H, by 5.57 kcal/mol more stable than the CH3COO-:m9GuaN3H complex, and coordination of Na+ with the O6 and N7 atoms reduces this energy difference to 2.57 kcal/mol. Such a coordination of Na+ with tautomer m9GuaN3H therewith decreases its relative energy only to 13.31 kcal/mol. Non-additivity of the two ligands contributions to the 8-times reduction of the relative energy of the high energy tautomer in the CH3COO-:m9GuaN3H:Na+(O6,N7) triple complex was concluded, the role of CH3COO- being dominant. Besides, coordination with Na+ resulted in an iminoproton transfer from the base to CH3COO- in the triple complexes of both tautomers, according to calculations in vacuum. Biological significance of the results is noticed.     

Synergistic effects in the designs of neuraminidase ligands: Analysis from docking and molecular dynamics studies

Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC₅₀ value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs.     

1H NMR spectroscopic characterization of binary and ternary complexes of cobalt(II) carboxypeptidase A with inhibitors

The binding of L- and D-phenylalanine and carboxylate inhibitors to cobalt(II)-substituted carboxypeptidase A, Co(II)CPD (E), in the presence and absence of pseudohalogens (X = N3-, NCO-, and NCS-) has been studied by 1H NMR spectroscopy. This technique monitors the proton signals of histidine residues bound to cobalt(II) and is therefore sensitive to the interactions of inhibitors that perturb the coordination sphere of the metal. Enzyme-inhibitor complexes, E.I, E.I2, and E.I.X, each with characteristic NMR features, have been identified. Thus, for example, L-Phe binds close to the metal ion to form a 1:1 complex, whereas D-Phe binds stepwise, first to a nonmetal site and then to the metal ion to form a 2:1 complex. Both acetate and phenylacetate also form 2:1 adducts stepwise with the enzyme, but beta-phenylpropionate gives a 2:1 complex without any detectable 1:1 intermediate. N3-, NCO-, and NCS- generate E.I.X ternary complexes directly with Co(II)CPD.L-Phe and indirectly with the D-Phe and carboxylate inhibitor 2:1 complexes by displacing the second moiety from its metal binding site. The NMR data suggest that when the carboxylate group of a substrate or inhibitor binds at the active site, a conformational change occurs that allows a second ligand molecule to bind to the metal ion, altering its coordination sphere and thereby attenuating the bidentate behavior of Glu-72. The 1H NMR signals also reflect alterations in the histidine interactions with the metal upon inhibitor binding. Isotropic shifts in the signals for the C-4 (c) and N protons (a) of one of the histidine ligands are readily observed in all of these complexes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thermodynamic penalty arising from burial of a ligand polar group within a hydrophobic pocket of a protein receptor

Here, we examine the thermodynamic penalty arising from burial of a polar group in a hydrophobic pocket that forms part of the binding-site of the major urinary protein (MUP-I). X-ray crystal structures of the complexes of octanol, nonanol and 1,8 octan-diol indicate that these ligands bind with similar orientations in the binding pocket. Each complex is characterised by a bridging water molecule between the hydroxyl group of Tyr120 and the hydroxyl group of each ligand. The additional hydroxyl group of 1,8 octan-diol is thereby forced to reside in a hydrophobic pocket, and isothermal titration calorimetry experiments indicate that this is accompanied by a standard free energy penalty of +21 kJ/mol with respect to octanol and +18 kJ/mol with respect to nonanol. Consideration of the solvation thermodynamics of each ligand enables the "intrinsic" (solute-solute) interaction energy to be determined, which indicates a favourable enthalpic component and an entropic component that is small or zero. These data indicate that the thermodynamic penalty to binding derived from the unfavourable desolvation of 1,8 octan-diol is partially offset by a favourable intrinsic contribution. Quantum chemical calculations suggest that this latter contribution derives from favourable solute-solute dispersion interactions.     

A density functional theory investigation of the interaction of the tetraaqua calcium cation with bidentate carbonyl ligands

Calcium complexes with bidentate carbonyl ligands are important in biological systems, medicine and industry, where the concentration of Ca²⁺ is controlled using chelating ligands. The exchange of two water molecules of [Ca(H₂O)₆]²⁺ for one bidentate monosubstituted and homo disubstituted dicarbonyl ligand was investigated using the B3LYP/6-311++G(d,p) method. The ligand substituents NH₂, OCH₃, OH, CH₃, H, F, Cl, CN and NO₂ are functional groups with distinct electron-donating and -withdrawing effects that bond directly to the sp² C atom of the carbonyl group. The geometry, charge and energy characteristics of the complexes were analyzed to help understand the effects of substituents, spacer length and chelation. Coordination strength was quantified in terms of the enthalpy and free energy of the exchange reaction. The most negative enthalpies were calculated for the coordination of bidentate ligands containing three to five methylene group spacers between carbonyls. The chelate effect contribution was analyzed based on the thermochemistry. The electronic character of the substituent modulates the strength of binding to the metal cation, as ligands containing electron-donor substituents coordinate stronger than those with electron-acceptor substituents. This is reflected in the geometric (bond length and chelating angle), electronic (atomic charges) and energetic (components of the total interacting energy) characteristics of the complexes. Energy decomposition analysis (EDA)—an approach for partitioning of the energy into its chemical origins—shows that the electrostatic component of the coordination is predominant, and yields relevant contribution of the covalent term, especially for the electron-withdrawing substituted ligands. The chelate effect of the bidentate ligands was noticeable when compared with substitution by two monodentate ligands.

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Graphical abstract The affinity of 18 bidentate carbonyl ligands toward the [Ca(H₂O)₄]²⁺ cation is evaluated in terms of energetic, geometric and electronic parameters of the isolated ligands and the substituted aqua complexes. The electronic effects—inductive and mesomeric—intrinsic to the molecular structure of each ligand are found to modulate the strength of the metal-ligand interaction. The effects of polysubstitution, chelation and the length of the alkyl spacers between the anchor points of the ligand are also analyzed.