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 leg D-glucose exists overwhelmingly as a C-4(1) 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, T-1 rho measurements, T-1 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 C-4(1), and S-O(2) conformers. C-13 NMR line shape analysis yields a Delta H dagger of 40 kJ mol(-1) and a Delta S double dagger of 31 J mol(-1) K-1: for the C-4(1) --> S-0(2) interconversion and a Delta H double dagger of 31 kJ mol(-1) and a Delta S double dagger of 13 J mol(-1) K-1 for the S-0(2) --> C-4(1) interconversion. This corresponds to exchange rates of 22 and 128 MHz, respectively, at room temperature. [References: 27]

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