1 research outputs found
Hydroxyl-Proton Hydrogen Bonding in the Heparin Oligosaccharide Arixtra in Aqueous Solution
Heparin is best known for its anticoagulant
activity, which is
mediated by the binding of a specific pentasaccharide sequence to
the protease inhibitor antithrombin-III (AT-III). Although heparin
oligosaccharides are thought to be flexible in aqueous solution, the
recent discovery of a hydrogen bond between the sulfamate (NHSO<sub>3</sub><sup>–</sup>) proton and the adjacent 3-<i>O</i>-sulfo group of the 3,6-<i>O</i>-sulfated <i>N</i>-sulfoglucosamine residue of the Arixtra (fondaparinux sodium) pentasaccharide
demonstrates that definable elements of local structure are accessed.
Molecular dynamics simulations of Arixtra suggest the presence of
additional hydrogen bonds involving the C3-OH groups of the glucuronic
acid and 2-<i>O</i>-sulfo-iduronic acid residues. NMR measurements
of temperature coefficients, chemical shift differences, and solvent
exchange rate constants provide experimental confirmation of these
hydrogen bonds. We note that the extraction of rate constants from
cross-peak buildup curves in 2D exchange spectroscopy is complicated
by the presence of radiation damping in aqueous solution. A straightforward
model is presented that explicitly takes into account the effects
of radiation damping on the water proton relaxation and is sufficiently
robust to provide an accurate measure of the proton exchange rate
between the analyte hydroxyl protons and water