SOLUTION DYNAMICS OF THE 1,2,3,4,6-PENTA-O-ACETYL-ALPHA-D-IDOPYRANOSERING

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 bi nd to antithrombin III is a highly sulfated pentasaccharide which cont ains a 2-O-sulfo-alpha-L-idopyranosyluronic acid residue. The idopyran osyl residue has the unusual property of existing in the solution stat e as a mixture of ring conformers. Whereas most hexopyranose sugars ex ist as a single chair conformer leg D-glucose exists overwhelmingly as a C-4(1) chair), the idopyranosyl ring is known to rapidly exchange b etween at least two and often more distinct conformations, depending o n 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 he parin is related to its binding specificity. In the past, coupling con stants 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, T-1 rho measurements, T-1 and NOE measurements and spectral density mappin g, which have been used to study the dynamics of conformer interconver sion in model compounds related to idose and glucose. The findings pre sented 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 equilibri um consisting of the C-4(1), and S-O(2) conformers. C-13 NMR line shap e analysis yields a Delta H dagger of 40 kJ mol(-1) and a Delta S doub le dagger of 31 J mol(-1) K-1: for the C-4(1) --> S-0(2) interconversi on and a Delta H double dagger of 31 kJ mol(-1) and a Delta S double d agger of 13 J mol(-1) K-1 for the S-0(2) --> C-4(1) interconversion. T his corresponds to exchange rates of 22 and 128 MHz, respectively, at room temperature.