Glycosaminoglycan conformation: do aqueous molecular dynamics simulations agree with x-ray fiber diffraction?

Glycosaminoglycan-protein interactions are biologically important and requi re an appreciation of glycan molecular shape in solution, which is presentl y unavailable. In previous studies we found strong similarity between aqueo us molecular dynamics (MD) simulations and published x-ray diffraction refi nements of hyaluronan, We have applied a similar approach here to chondroit in and dermatan, attempting to clarify some of the issues raised by the x-r ay diffraction literature relating to chondroitin and dermatan sulfate. We predict that chondroitin has the same beta(1-->4) linkage conformation as h yaluronan, and that their average beta(1-->3) conformations differ. This is explained by changes in hydrogen-bonding across this linkage, resulting fr om its axial hydroxyl, causing a different sampling of left-handed helices in chondroitin (2.5- to 3.5-fold) as compared with hyaluronan (3,0- to 4.0- fold). Few right-handed helices, which lack intramolecular hydrogen-bonds, were sampled during our MD simulations. Thus, we propose that the 8-fold he lix observed in chondroitin-6-sulfate, represented in the literature as an 8(3) helix (right-handed), though it has never been refined, is more likely to be 8(5) (left-handed) helix. Molecular dynamics simulations implied tha t C-4(1) and S-2(0), but not C-1(4), forms of iduronate could be used in re finements of dermatan x-ray fiber diffraction patterns. Current models of 8 -fold dermatan sulfate chains containing 4C1 iduronate refine to right-hand ed helices, which possess no intramolecular hydrogen-bonds. However, MD sim ulations predict that models containing S-2(0) iduronate could provide bett er (85 helix) starting structures for refinement. Thus, the 8-fold dermatan sulfate refinement (83 helix) could be in error.