The kinetics and mechanism of the complexation of La3+ and Cu2+ ions with desferrioxamine B (H4dfb+) and N-methylacetohydroxamic acid (NMHA) in aqueous medium were studied by stopped-flow and 1H NMR methods. The equilibrium constants for reactions (M n+ + HA ⇄ MA(n-1)+ + H+) of NMHA with Cu2+ and La3+ were determined by the combined pH−spectral titration method at 25 ± 0.1 °C as (1.58 ± 0.02) × 10-1 and (3.5 ± 0.2) × 10-4, respectively. In aqueous solution of 2 M ionic strength, the kinetic parameters for complexation of La3+ and Cu2+ with NMHA were determined as k(25 °C) = 3.0 ± 0.3 s-1, ΔH ⧧ = 76 ± 3 kJ mol-1, ΔS ⧧ = 19 ± 7 J K-1 mol-1, ΔV ⧧ = +5.3 ± 0.5 cm3/mol and k(25 °C) = 3.4 ± 0.2 s-1, ΔH ⧧ = 69 ± 1 kJ mol-1, ΔS ⧧ = −3 ± 3 J K-1 mol-1, ΔV ⧧ = +5.0 ± 0.5 cm3/mol, whereas with H4dfb+ they were determined as k(25 °C) = 2.9 ± 0.3 s-1, ΔH ⧧ = 76 ± 1 kJ mol-1, ΔS ⧧ = 34 ± 4 J K-1 mol-1, ΔV ⧧ = +5.2 ± 0.5 cm3/mol; and k(25 °C) = 3.0 ± 0.4 s-1, ΔH ⧧ = 72 ± 1 kJ mol-1, ΔS ⧧ = 5 ± 2 J K-1 mol-1, ΔV ⧧ = +3.4 ± 0.2 cm3/mol, respectively. The rotation about the C−N hydroxamate bonds in NMHA and H4dfb+ is characterized by k(25 °C) = 11 ± 2 s-1, ΔH ⧧ = 76 ± 5 kJ mol-1, ΔS ⧧ = 31 ± 16 J K-1 mol-1, Δr V (cis⇄trans) = +1.5 ± 0.8 cm3/mol, k trans→cis(25 °C) = 2.8 ± 0.5 s-1, ΔV ⧧ trans→cis = +12 ± 4 cm3/mol and by k(25 °C) = 9 ± 1 s-1, ΔH ⧧ = 69 ± 6 kJ mol-1, ΔS ⧧ = 6 ± 18 J K-1 mol-1, Δr V (cis⇄trans) = +0.6 ± 0.3 cm3/mol, k trans→cis(25 °C) = 2.6 ± 0.3 s-1, ΔV ⧧ trans→cis = +5 ± 2 cm3/mol, respectively. The results suggest that the slow rotation around the hydroxamate C−N bond is the rate-determining step for the complexation reactions.
The conformation of the peptidoglycan monomer (PGM) from Brevibacterium divaricatum was determined in aqueous solution using a combined approach by 2D NMR spectroscopy, restrained simulated annealing, and molecular dynamics (MD) calculations. MD simulations in water without experimental constraints provided insights into the structure and dynamics of this glycopeptide. Hierarchical cluster analyses for conformer classifications were performed using a global molecular shape descriptor (CoMFA steric fields). Principal component analysis was subsequently employed to extract orthogonal principal conformational properties. Correlated dihedral angle mobilities were identified using a dynamic cross correlation map. The calculation of radial distribution functions for all polar protons of the molecule leads to additional information about the solvation of PGM in a protic solvent, while autocorrelation functions for dihedral angle fluctuations were used to monitor dynamic processes in different regions. From simulated annealing, a set of 11 conformers was obtained, all characterized by a well-defined extended N-terminal peptide part additionally stabilized by the bound disaccharide; the C-terminal part, on the other hand, exhibits more conformational flexibility in agreement with experimental data and MD simulations. The disaccharide conformation is in agreement with the conformational minimum computed for the model disaccharide 3-O-Me-4-O-βGlcNAc-αMurNAc using various force fields. Not only the interglycosidic bond but also the glycopeptide linkage exists in a single, well-defined conformation, for which no conformational changes can be detected during the MD simulations. In contrast, conflicting experimental data for the N-acetyl group of GlcNAc could be explained using a conformer population analysis based on ROE intensities and coupling constants accounting for a conformational equilibrium with one dominantly populated rotamer.
Desferrioxamine B, Hadfb, is a naturally occurring trishydroxamic acid used by numerous microorganisms as a strong and selective chelator for ferric ions.1•2 In neutral aqueous media, Fbdfb is fully protonated (structure I). Deprotonation of its three hydroxamic acids leads to the formation of a hexadentate ligand that is capable to complete the coordination shell of iron(III). A complex between desferrioxamine B and ferric ion is a siderophore named ferrioxamine B.Owing to desferrioxamine B's commercial availability,3 the mechanism of hydrolysis of ferrioxamine B is probably the most extensively studied of all siderophores.4-9 The mechanistic behavior forms a basis for understanding the biologically crucial unwrapping process in neutral or weak acid media, interchange processes,10 and catalyzed hydrolyses.11•12The hydrolysis of the tris(monohydroxamato)iron(III) complexes that were used as models for siderophores, proceeds through three distinct, proton-concentration dependent, kinetic steps.13•14 Each step corresponds to the stepwise dissociation of one of the coordinated hydroxamate ligands and involves protonation of the hydroxamate N-O group. On the other hand, the results obtained in two independent laboratories agree that Fe(Hdfb)+ undergoes full hydrolysis through at least four distinguishable kinetic steps.5•8 The first, third, and fourth steps were found to be proton-concentration dependent, whereas the second step does not involve protonation of ferrioxamine B. It was suggested that dechelation of the second hydroxamato group in Fe(Hdfb)+ proceeds in two steps.Caudle and Crumbliss14 have recently proposed that this discrepancy is caused by the slow rate of rotation around the middle hydroxamate C-N bond in partially unwrapped ferri-(1) Crumbliss, A. L. In Handbook of Microbial Iron Chelates', Winkel-
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