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

Abstract

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 Δ4,5-unsaturated uronate (ΔUA) residues. ΔUA residues frequently arise from the enzymatic digestion of heparin and heparin sulfate. Simulations of disaccharides containing ΔUA 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.

Gas-Phase Analysis of the Complex of Fibroblast GrowthFactor 1 with Heparan Sulfate: A Traveling Wave Ion Mobility Spectrometry (TWIMS) and Molecular Modeling Study

“…Topology and coordinate files for each system were generated using the tleap program, employing the ff99SB [52] and GLYCAM06 (version j) [53, 54] parameters for the protein and GAGs, respectively. Each system underwent energy minimization (1000 steps) in implicit solvent (IGB = 2).…”

The gram‐negative outer membrane modeler: Automated building of lipopolysaccharide‐rich bacterial outer membranes in four force fields

“…Another option is the CHARMM‐GUI Martini Maker, which currently offers two Escherichia coli LPS molecules (Re and Ra LPS) for the MARTINI Coarse‐Grained force field but does not, at present, support any other species. Some glycolipid and glycan modeling tools can also be used to model LPS molecules, such as doGlycans for the AMBER/GLYCAM and OPLS force fields; however, these methods are not able to construct LPS‐containing bilayers, either homogeneous or mixed. As such, apart from CHARMM‐GUI, there are very limited options to automatically create LPS‐containing membranes with force fields or molecules outside the aforementioned systems (e.g., GROMOS, or MARTINI with LPSs from species other than E. coli ), even though valid Lipid A and LPS parameters exist .…”

Perspective on computational simulations of glycosaminoglycans

“…The reader is also directed to a recent review on carbohydrate force field development for additional information . Of the three, GLYCAM supports a vast library of saccharide sequences, which includes nonreducing‐end unsaturated GAG chains …”

“…Furthermore, the GLYCAM06 parameter set had well‐established parameters for GAGs, except for inability to address unsaturated uronic acid monosaccharides (ΔUA). Recently, GLYCAM06 was updated with a more generalized parameter set to model N ‐ and O ‐sulfation, ΔUA residues, neutral and protonated GlcN, IdoA, and GlcA residues . MM calculations were carried out using AMBER11 and TIP3P water box, and simulation predictions were comparable with experimental NMR scalar coupling and NOE measurements.…”

“…Simulations for a hexasaccharide sequence were also performed and compared with monosaccharide results . Finally, the validation of new GLYCAM06 parameter set (discussed above) included variably sulfated GAG di‐ and tri‐saccharides containing terminal ΔUA residue, in which the initial structures were built using the LEaP module of AMBER12 and TIP3P water molecule for solvation . These newly developed parameters have been employed for conformational study of eight HS hexasaccharides containing variable sulfated GlcN residues (2‐ O ‐, 3‐ O ‐ and 6‐ O ‐substitution) to elucidate influence on neighboring IdoA and IdoA2S residues …”