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.