Structure of the radiation protection agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721)

Karle, Jean M.; Karle, Isabella L.

doi:10.1107/s0108270187007911

Cited by 4 publications

(2 citation statements)

References 10 publications

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“…There appear to be very few reports and even fewer with structural proof on the formation of double zwitterions, mostly on diaminoalkylphosphorothioic acids and small peptides . Deprotonation of the phenol group and protonation of the imine nitrogen in salicylaldimine-type compounds to give a zwitterion are rare ,, in view of the vast number of salicylaldimine derivatives.…”

Section: Resultsmentioning

confidence: 99%

N-o-Vanillylidene-l-histidine: Experimental Charge Density Analysis of a Double Zwitterionic Amino Acid Schiff-Base Compound

Drašković¹,

Bogdanović²,

Neelakantan³

et al. 2010

Crystal Growth & Design

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A double zwitterionic Schiff base was synthesized using the amino acid L-histidine and o-vanillin (2-hydroxy-3methoxy benzaldehyde). Both the phenol and carboxyl groups are deprotonated, and the imine nitrogen atom and histidineimidazole ring are protonated to give the double zwitterion with an intramolecular (imine)N-H þ 3 3 3 -O(phenol) hydrogen bond (ketoamine form). Such a ketoamine form in a double zwitterion is assumed in the catalytic cycle of enzymatic transformations of amino acids with the cofactor (vitamin B6) pyridoxal-5 0 -phosphate (PLP). A high-resolution, lowtemperature, single-crystal X-ray diffraction data set on N-o-vanillylidene-L-histidine (also named 3-methoxysalicylidene-Lhistidine or N-(2-oxy-3-methoxy-benzylidene)-L-histidine, OVHIS) is used in the analysis of molecular electrostatic properties and intermolecular interactions. All oxygen atoms in the molecule (four in total) are mutually almost coplanar and located (externally) on the same side of molecule. These four O atoms carry significant negative charge and form a large area of strong negative electrostatic potential (appropriate for bonding to a metal atom). The protonated and, thus, positively charged imidazole ring is situated on the opposite side of the molecule from the area of the O atoms. Consequently, the OVHIS molecule is highly polarized and has a very high molecular dipole moment of 42.4 D in the solid state (calculated from experimental X-ray data). Two strong intermolecular charge-assisted N-H þ 3 3 3 -O hydrogen bonds (with H 3 3 3 O distances of 1.61 A ˚) together with other D-H 3 3 3 O interactions (D = N, C) contribute to a large molecular dipole enhancement which occurs upon crystallization. The topologies of the bonding within the molecule as well as its hydrogen bonds have been investigated according to Bader's quantum theory of atoms in molecules (QTAIM). 1 H solid-state magic angle spinning nuclear magnetic resonance (MAS NMR) was used to confirm the zwitterionic structure in the solid state.

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Section: Resultsmentioning

confidence: 99%

N-o-Vanillylidene-l-histidine: Experimental Charge Density Analysis of a Double Zwitterionic Amino Acid Schiff-Base Compound

Drašković¹,

Bogdanović²,

Neelakantan³

et al. 2010

Crystal Growth & Design

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“…These additional parameters are adjusted to reproduce bond lengths and bond angles for analogous organic thiophosphate compounds in crystals from the Cambridge Structural Database. 27,28 Partial atomic charges are derived from HF/6-31+G * electrostatic potentials for the optimized structure of CH 3 SPO 2− 3 using the Besler-Merz-Kollman method implemented in Gaussian 92 (Frisch et al 47 ). The van der Waals parameters are taken from the CHARMM 22 force field for similar atom types.…”

Section: Computational Procedures Potential Functionsmentioning

confidence: 99%

Hydrogen-bonding interactions in the active site of a low molecular weight protein-tyrosine phosphatase

Alhambra

Gao

2000

J. Comput. Chem.

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Molecular dynamics simulation of the Michaelis complex, phospho-enzyme intermediate, and the wild-type and C12S mutant have been carried out to examine hydrogen-bonding interactions in the active site of the bovine low molecular weight protein-tyrosine phosphatase (BPTP). It was found that the S γ atom of the nucleophilic residue Cys-12 is ideally located at a position opposite from the phenylphosphate dianion for an inline nucleophilic substitution reaction. In addition, electrostatic and hydrogen-bonding interactions from the backbone amide groups of the phosphate-binding loop strongly stabilize the thiolate anion, making Cys-12 ionized in the active site. In the phospho-enzyme intermediate, three water molecules are found to form strong hydrogen bonds with the phosphate group. In addition, another water molecule can be identified to form bridging hydrogen bonds between the phosphate group and Asp-129, which may act as the nucleophile in the subsequent phosphate hydrolysis reaction, with Asp-129 serving as a general base. The structural difference at the active site between the wild-type and C12S mutant has been examined. It was found that the alkoxide anion is significantly shifted toward one side of the phosphate binding loop, away from the optimal position enjoyed by the thiolate anion of the wild-type enzyme in an S N 2 process. This, coupled with the high pK a value of an alcoholic residue, makes the C12S mutant catalytically inactive. These molecular dynamics simulations provided details of hydrogen bonding interactions in the active site of BPTP, and a structural basis for further studies using combined quantum mechanical and molecular mechanical potential to model the entire dephosphorylation reaction by BPTP.

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Computational modeling of catalysis and binding in low-molecular-weight protein tyrosine phosphatase

Kolmodin

Åqvist

1999

Int. J. Quant. Chem.

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ABSTRACT:The energetics of substrate dephosphorylation in the low-molecularweight protein tyrosine phosphatase is studied with the empirical valence bond method in combination with molecular dynamics free energy perturbation simulations. Different mechanisms corresponding to different charge states of the reacting groups are examined. We find very similar activation barriers for attack of the reactive cysteine anion on the mono-and dianion of phenylphosphate, although this reaction step is more exothermic in the latter case. This result is found to be consistent with calculations of the relative binding affinities of the protonated and unprotonated substrate, which clearly indicate that the substrate dianion will not bind when the reactive cysteine is in its thiolate form. The reaction with monoanionic substrate is found to have an activation barrier that is more than 15 kcalrmole lower than that of the dianion when the binding step is taken into account. We also find that leaving group protonation by Asp129 has to be concerted with bond cleavage. The calculated overall activation energy for substrate dephosphorylation according to the favored mechanism is in good agreement with experimental data.

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Structure of the radiation protection agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721)

Cited by 4 publications

References 10 publications

N-o-Vanillylidene-l-histidine: Experimental Charge Density Analysis of a Double Zwitterionic Amino Acid Schiff-Base Compound

N-o-Vanillylidene-l-histidine: Experimental Charge Density Analysis of a Double Zwitterionic Amino Acid Schiff-Base Compound

Hydrogen-bonding interactions in the active site of a low molecular weight protein-tyrosine phosphatase

Computational modeling of catalysis and binding in low-molecular-weight protein tyrosine phosphatase

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