Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans

Glycosaminoglycans (GAGs) are an important class of carbohydrates that serve critical roles in blood clotting, tissue repair, cell migration and adhesion, and lubrication. The variable sulfation pattern and iduronate ring conformations in GAGs influence their polymeric structure and nature of interaction. This study characterizes several heparin-like GAG disaccharides and tetrasaccharides using NMR and molecular dynamics simulations to assist in the development of parameters for GAGs within the GLYCAM06 force field. The force field additions include parameters and charges for a transferable sulfate group for O-and N-sulfation, neutral (COOH) forms of iduronic and glucuronic acid, and 4,5-unsaturated uronate (UA) residues. UA residues frequently arise from the enzymatic digestion of heparin and heparin sulfate. Simulations of disaccharides containing UA reveal that the presence of sulfation on this residue alters the relative populations of ¹H₂ and ²H₁ ring conformations. Simulations of heparin tetrasaccharides containing N-sulfation in place of N-acetylation on glucosamine residues influence the ring conformations of adjacent iduronate residues.