Solution dynamics of the 1,2,3,4,6-penta-O-acetyl-alpha-D-idopyranose ring.
The anticoagulant properties of heparin are thought to derive from the inhibition of thrombin and other coagulation-related proteases by the binding of heparin to cofactors such as antithrombin III and heparin cofactor II. The apparent minimum native heparin sequence which can bind to antithrombin III is a highly sulfated pentasaccharide which contains a 2-O-sulfo-alpha-L-idopyranosyluronic acid residue. The idopyranosyl residue has the unusual property of existing in the solution state as a mixture of ring conformers. Whereas most hexopyranose sugars exist as a single chair conformer (eg D-glucose exists overwhelmingly as a (4)C1 chair), the idopyranosyl ring is known to rapidly exchange between at least two and often more distinct conformations, depending on type and number of substituents (hydroxyl, carboxyl, sulfate, etc.) and solvent conditions (solvent pH, salt concentration, temperature). It is believed that this flexibility of the idopyranosyl residue in heparin is related to its binding specificity. In the past, coupling constants and molecular dynamics have been used to estimate the relative populations of conformers in iduronate and related compounds. Here we report extensive NMR measurements, including line shape analysis, T1p measurements, T1 and NOE measurements and spectral density mapping, which have been used to study the dynamics of conformer interconversion in model compounds related to idose and glucose. The findings presented here indicate that 1,2,3,4,6-penta-O-acetyl-alpha-D-idopyranose can be reasonably well described as existing in a two-state equilibrium consisting of the (4)C1 and (0)S2 conformers. (13)C NMR line shape analysis yields a deltaH+ of 40 kJ mol(-1) and a deltaS++ of 31 J mol(-1) K(-1) for the (4)C1 --> (0)S2 interconversion and a deltaH++ of 31 kJ mol(-1) and a deltaS++ of 13 J mol(-1) K(-1) for the (0)S2 --> (4)C1 interconversion. This corresponds to exchange rates of 22 and 128 MHz, respectively, at room temperature.
Horita
D A
DA
Department of Chemistry, University of Wisconsin, Madison 53706, USA.
Hajduk
P J
PJ
Lerner
L E
LE
D000107:Acetylation; D002151:Calorimetry; D002236:Carbohydrate Conformation; D006601:Hexoses / Q000737:chemistry*; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D012996:Solutions; D012997:Solvents; D013816:Thermodynamics
D006601:Hexoses; D012996:Solutions; D012997:Solvents