Deprotonation Of Amide Nitrogen Research Articles

The interaction of half-sandwich (η5-Cp*)Rh(III) cation with histidine containing peptides and their ternary species with (N,N) bidentate ligands

Our goal was to explore the possible interactions of the potential metallodrug (η5-Cp*)Rh(III) complexes with histidine containing biomolecules (peptides/proteins) in order to understand the most important thermodynamic factors influencing the biospeciation and biotransformation of (η5-Cp*)Rh(III) complexes. To this end, here we report systematic solution thermodynamic and solution structural study on the interaction of (η5-Cp*)Rh(III) cation with histidine containing peptides and their constituents ((N-methyl)imidazole, GGA-OH, GGH-OH, histidine-amide, HGG-OH, GHG-NH2), based on extensive 1H NMR, ESI-MS and potentiometric investigations. The comparative evaluation of our data indicated that (η5-Cp*)Rh(III) cation is able to induce the deprotonation of amide nitrogen well below pH 7. Consequently, at physiological pH the peptides are coordinated to Rh(III) by tridentate manner, with the participation of amide nitrogen. At pH 7.4 the (η5-Cp*)Rh(III) binding affinity of peptides follow the order GGA-OH < < GGH-OH < < histidine-amide < HGG-OH < GHG-NH2, i.e. the observed binding strength essentially depends on the presence and position of histidine within the peptide sequence. We also performed computational study on the possible solution structures of complexes present at near physiological pH. At pH 7.4 all histidine containing peptides form ternary complexes with strongly coordinating (N,N) bidentate ligands (ethylenediamine or bipyridyl), in which the peptides are monodentately coordinated to Rh(III) through their imidazole N1‑nitrogens. In addition, the strongest chelators histidine-amide, HGG-OH and GHG-NH2 are also able to displace these powerful bidentate ligands from the coordination sphere of Rh(III).

Versatile coordination and C-H activation of a multi-donor phosphinoferrocene carboxamide ligand in Pd(ii) complexes.

A multi-donor phosphinoferrocene carboxamide, FcCONHCH2CH2PPh2 (1, Fc = ferrocenyl), was prepared, converted into the corresponding phosphine oxide 1O and phosphine selenide 1Se and, mainly, studied as a ligand in Pd(ii) complexes. In its native form, amide 1 preferentially coordinated soft Pd(ii) as a simple phosphine, giving rise to mixtures of cis and trans-[PdX2(1-κP)2] (2; X = Cl (a), Br (b), and I (c)), wherein the isomer ratios depended on the auxiliary halide ligand or, alternatively, to the complex [(LNC)PdCl(1-κP)] (6, LNC = 2-[(dimethylamino)methyl-κN]phenyl-κC1). This coordination mode was nevertheless easily changed when creating a vacant coordination site at the palladium. Thus, treatment of 2a with NH4[PF6] in the presence of free 1 produced [PdCl(1-κP)3][PF6] (3), while complete halogen removal with a Ag(i) salt led to cationic complexes cis-[Pd(1-κ2O,P)2]X2 (4, X = CF3SO3 (a), ClO4 (b), BF4 (c)) or [(LNC)Pd(1-κ2O,P)]X (7a and 7b), containing seven-membered O,P-chelate rings. In contrast, amide nitrogen deprotonation with KOt-Bu followed by spontaneous intramolecular halogen substitution resulted in the transformation of 6 into the chelate complex [(LNC)Pd{(1- H)-κ2N,P}] (8) featuring a five-membered N,P-chelate ring, and in the conversion of 2a and 2b into the product of C-H bond activation [Pd{Fe(η5-C5H3CONCH2CH2PPh2-κ3C,N,P)(η5-C5H5)}(1-κP)] (5), with doubly chelating deprotonated 1. Importantly, complexes 2-4-5 and 6-7-8 were mutually interconverted in triads (by protonation/deprotonation and by halide addition/abstraction), which highlights the flexible coordination and chemical stability of ligand 1. The crystal structures of 1O·½H2O, trans-2a·MeCN, trans-2b·3C2H4Cl2, trans-2c·2.5C2H4Cl2, 4a·CH2Cl2, 5·3CHCl3·Et2O, and 8 were determined by single-crystal X-ray diffraction analysis, and the representative compounds were studied by cyclic voltammetry.

Copper(II) interaction with peptide fragments of histidine–proline-rich glycoprotein: Speciation, stability and binding details

GHHPH is the peptide repeat present in histidine–proline rich glycoprotein (HPRG), a plasma glycoprotein involved in angiogenesis process. The copper(II) ions interaction with mono (Ac-GHHPHG-NH2) and its bis-repeat (Ac-GHHPHGHHPHG-NH2) was investigated by means of potentiometric and spectroscopic techniques. To single out the copper(II) coordination environments of different species formed with Ac-GHHPHG-NH2, three single point mutated peptides were also synthesized and their ability to coordinate Cu2+ investigated. Ac-GHHPHG-NH2 binds Cu2+ by the imidazole side chain and the amide nitrogen deprotonation that takes place towards the N-terminus. The bis-repeat is able to bind Cu2+ more efficiently than Ac-GHHPHG-NH2. This difference is not only due to the number of His residues in the sequence but also to the different binding sites. In fact, the comparison of the potentiometric and spectroscopic data of the copper(II) complexes with a bis-repeatPeg construct Ac-(GHHPHG)-Peg-(GHHPHG)-NH2 and those of the metal complexes with Ac-HGHH-NH2, indicates that the central HGHH amino acid sequence is the main copper(II) binding site.

Theoretical Studies of Chromophore Maturation in the Wild-Type Green Fluorescent Protein: ONIOM(DFT:MM) Investigation of the Mechanism of Cyclization

The availability of a gene encoding green fluorescence immediately stimulates interest in the puzzle of autocatalytic formation of the green fluorescent protein (GFP) chromophore. Numerous experimental and theoretical studies have indicated that cyclization is the first and most important step in the maturation process of the GFP. In our previous paper based on cluster models [J. Phys. Chem. B2010, 114, 9698-9705], two possible mechanisms have been investigated with the conclusion that the backbone condensation initiated by deprotonation of the Gly67 amide nitrogen is easier than deprotonation of the Tyr66 α-carbon. However, the impact of the protein environment on the reaction mechanism remains to be explored. In this paper, we investigated the two possible mechanisms with inclusion of protein environmental effects by using molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) calculations. Our calculations reveal no hydrogen bonding network that would facilitate deprotonation of the amide nitrogen of Gly67, although it is the lower energy pathway in the cluster model system. Contrastingly, there is a hydrogen bonding network between Tyr66 α-carbon and Glu222, which is in good agreement with X-ray data. The ONIOM studies show that proton transfer from Tyr66 α-carbon to Glu222 is a long-distance charge transfer process. The charge distribution of the MM region has a significant perturbation to the wave function for the QM region, with the QM energy for the proton transfer product being increased under the influence of the electrostatic protein environment. The barrier for the rate-limiting step in cyclization is quite high, about 40.0 kcal/mol in the case of ONIOM-EE.

Aromatic Interactions in Unusual Backbone Nitrogen-Coordinated Zinc Peptide Complexes: A Crystallographic and Spectroscopic Study

A series of zinc complexes with dipeptide ligands of the type Dpg-Xaa was synthesized, where Dpg is dipicolylglycine and Xaa is phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), 2-naphthylalanine (Nal), or glycine (Gly). It was shown that aromatic interactions promote the unusual coordination of an anionic peptide backbone nitrogen atom to zinc. This binding mode was, for the first time, characterized by X-ray structure analyses of the electrically neutral complexes [(Dpg-Phe)(-H)Zn], [(Dpg-Tyr)(-H)Zn], [(Dpg-Trp)(-H)Zn], and [(Dpg-Nal)(-H)Zn]. The pKa values for amide nitrogen deprotonation were determined by 1H NMR titrations {[(Dpg-Phe)Zn], 7.17; [(Dpg-Tyr)Zn], 6.85; [(Dpg-Trp)Zn], 6.85; [(Dpg-Nal)Zn], 6.64; [(Dpg-Gly)Zn], 8.54}. It was calculated that aromatic interactions contribute ca. -8 to -11 kJ/mol of stabilizing free enthalpy changes in the derivatives with aromatic amino acid side chains. These are the first quantitative data obtained for crystallographically characterized metal complexes. A comparison with the literature shows that it is difficult to distinguish between pi-cation attraction and pi-pi stacking. However, it is evident that modification of small peptides with synthetic pyridine ligands enhances their ability to stabilize secondary structures by noncovalent interactions. This is an important consideration for the design of biomimetic metallopeptides.

Copper(ii) complexes of amino acid derivatives of the bis(imidazol-2-yl)methyl residue

Copper(II) complexes of amino acid derivatives of bis(imidazol-2-yl)methylamine (BIMA), α-Asp–BIMA, α-Glu–BIMA, γ-Glu–BIMA and β-Ala–BIMA, were studied by potentiometric, UV-VIS and EPR techniques. The bis(imidazol-2-yl)methyl residue is the main binding site in strong acidic medium in all cases. The formation of ligand-bridged dinuclear [Cu2L2]2+ species was detected in an equimolar solution of α-Asp–BIMA and γ-Glu–BIMA with binding of the N-terminal amino and carboxylate groups. The deprotonation of amide nitrogen takes place above pH 6 for the ligands containing an amide group in a chelatable position with terminal amino group (α-Asp–BIMA, α-Glu–BIMA and β-Ala–BIMA), resulting in the formation of dinuclear [Cu2H−2L2] species with imidazole bridging. For these 3 ligands, deprotonation of the pyrrole-type nitrogen was observed and the existence of a trinuclear species [Cu3H−4L2] was assumed in alkaline solution. This species contains negatively charged imidazolato bridges.

Thiolate anchor in organotin(iv) induced amide deprotonation: equilibrium and NMR spectroscopic studies on dimethyltin(iv) complexes formed with N-(2-mercaptopropionyl)glycine andl-alanyl-glycine

The coordination properties of the simple dipeptide L-alanyl-glycine (Ala-Gly) towards dimethyltin(IV) cation have been compared with its mercapto analogue N-(2-mercaptopropionyl)glycine (MPGly), using potentiometric, 1H and 13C NMR spectroscopic methods. The replacement of the terminal amino group of Ala-Gly by a thiol group (MPGly) induces fundamental changes in the coordination processes and in the speciation of metal complexes, though the composition of the species formed is identical. The considerably higher stability of the MPGly complexes is due to the outstanding affinity of dimethyltin(IV) cation toward sulfur donor atoms. In the MLH and ML complexes, formed in the acidic pH range, monodentate carboxylate and thiolate coordination has been observed for Ala-Gly and MPGly, respectively. Therefore, different donor groups in the case of the two ligands assist the metal promoted deprotonation of amide nitrogen. Our data provide the first example, that thiolate can act as an anchoring group in the diorganotin(IV) induced amide deprotonation.

Dimethyltin(IV) cation induced amide deprotonation of aspartic acid containing dipeptides †

The co-ordination behaviours of two dipeptides, glycyl-aspartic acid (Gly-Asp) and aspartyl-glycine (Asp-Gly), towards dimethyltin(IV) cations have been investigated by potentiometry and spectroscopic methods (1H and 13C NMR and Mössbauer). The formation of mononuclear complexes has been detected between pH 2 and 10, although the hydrolysed species are also present in the solution. On the basis of pH-metric and NMR data, the carboxylate groups are bound to the metal ion in the acidic pH range and act as anchoring groups for the metal-promoted deprotonation of amide nitrogens between pH 4 and 7. The complexes formed in this way are relatively inert on the NMR timescale in the case of both ligands, allowing their structural characterization by NMR spectroscopy. These species can be described with a trigonal bipyramidal structure having a {CO2−, N−amide, NH2} co-ordination, where the metal-bound carboxylate is very likely the C-terminal one. In spite of the constitutional differences, Asp-Gly and Gly-Asp form stable complexes with dimethyltin(IV) cation in the neutral pH range with identical structure and geometry.

Metal complexes of imidazole ligands containing histamine-like donor sets: equilibrium, solution structure and hydrolytic activity ‡

The equilibrium and structural properties of copper(II) and zinc(II) complexes of N,N′-di-L-histidylethane-1,2-diamine (dhen) and those of the strongly related histamine have been characterized by pH-metric and spectroscopic (UV/VIS, CD, EPR and NMR) methods. In both dhen systems a dimeric M2L2 species is dominant near the physiological pH, having bis(histamine-like) 2Nim, 2NH2 co-ordination. The MLH–2 complex, also formed in both systems above pH 10, has different structures with the two metal ions. A hydroxo mixed-ligand complex is formed in the case of zinc(II), while the base-consuming processes are assigned to metal-promoted deprotonation of amide nitrogens in the copper(II) system. Between these two dominant species (pH 7–10) tetrameric complexes are formed in each case (as suggested by the CD, EPR and NMR results), with the participation of imidazole-N1 (pyrrolic) nitrogen in the co-ordination. The catalytic activity of the zinc(II)-containing systems towards the hydrolysis of uridine 2′,3′-cyclic monophosphate as nuclease model has been examined. The zinc(II)–histamine complexes efficiently catalyse the hydrolysis. A kinetic study performed at different pH, concentrations and metal-to-ligand ratios, combined with the equilibrium data, revealed three reaction pathways involving Zn(OH), ZnL and ZnL(OH) complexes as active species, in order of activity ZnL Zn(OH) < ZnL(OH).

Specific binding of Cu 2+ and Ni 2+ ions by thioamide analogs of tetraalanine

Thioamide derivatives of short peptides are much more efficient ligands for Cu 2+ and Ni 2+ ions than their parent analogs. The most effective is the insertion of the thiocarbonyl group into the first, second, or third peptide linkage. In all of these cases, the sulfur atom is involved directly in metal ion binding, leading to the formation of very stable complexes. In all cases discussed, sulfur binding does not prevent an amide nitrogen deprotonation and its coordination to metal ion in basic solutions, although at the region close to physiological pH, sulfur is the basic donor for both Cu 2+ and Ni 2+ ions.

Binding ability of N-Para-amino-phenylsulfonyl derivatives of amino acids. Potentiometric and spectroscopic studies of Cu(II) complexes

N-Para-amino-phenylsulfonyl derivatives of amino acids are very effective ligands for Cu(II) ions. Potentiometric and spectroscopic results have shown that Cu(II) ions are able to deprotonate and bind to sulfonamide nitrogen below pH 5 to form stable mono- and bis-[N −, COO −] chelates. The basicity of sulfonamide nitrogen is lower than peptide amide nitrogen and no distinct anchoring site is necessary to promote the amide nitrogen deprotonation.

Copper(II) complexes of 2-carbamoylethyl derivatives of linear diamines. Crystallographic evidence for amido oxygen binding prior to deprotonation of amide nitrogens

There has been considerable interest in the coordination chemistry of linear and macrocyclic amides(1). Deprotonation of the amide nitrogen is known to occur with various metal ions and the sites of coordination are generally considered to be the carbonyl oxygen prior to deprotonation and the amide nitrogen after deprotonation. However, oxygen binding has generally been inferred from indirect evidence(2,3). We now report the results of some studies on the interaction of copper(II) with a series of 2-carbamoylethyl derivatives of linear diamines, namelyN,N′-bis(2-carbamoylethyl)ethylenediamine (1),N,N,N′,N′-tetrakis(2-carbamoylethyl)ethylenediamine (2)N,N′-bis(2-carbamoylethyl)trimethylenediamine (3) andN,N,N′,N′-tetrakis(2-carbamoylethyl)trimethylenediamine (4) which confirm carbonyl oxygen binding prior to amide deprotonation.

Binding ability of thiocarbonyl-containing dipeptides. Potentiometric and spectroscopic studies of copper(II) and nickel(II) coordination

Complex formation reactions of thioamide-containing dipeptides (Alat-Ala-OMe and Asp-Phet-NH 2) with copper(II) and nickel(II) were studied by the pH-metric and spectroscopic methods. Sulfur donation was established in acidic and neutral media, and it resulted in the enhanced stability of the respective complex species. Already, at pH < 3, the S to metal charge transfer band indicated the {NH 2S} coordination in cupric complexes. The high stability constants of CuA and CuA 2 complexes in comparison to respective complexes with glycine-amide (two and five orders, respectively) also indicate the involvement of sulfur in the metal ion coordination. The thiocarbonyl donor is involved in coordination of nickel(II) ions as well. The stability constants of respective complexes are enhanced, and, according to the spectroscopic data, the NiA 2 species is octahedral. It was also found that the coordination of thiocarbonyl donor although it is very effective, cannot prevent an amide nitrogen deprotonation and its coordination to metal ion in basic solutions. According to absorption and c.d. spectra in basic solutions, metal ions are bound to {NHi 2N −} donor sets, and resulting complexes MA 2H −2 are tetragonal for copper and square-planar for nickel ions.