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Abstract: The monosaccharide 2-O-sulfo-α-l-iduronic acid (IdoA2S) is one of the major components of glycosaminoglycans. The ability of molecular mechanics force fields to reproduce ring-puckering conformational equilibrium is important for the successful prediction of the free energies of interaction of these carbohydrates with proteins. Here we report unconstrained molecular dynamics simulations of IdoA2S monosaccharide that were carried out to investigate the ability of commonly used force fields to reproduce its ring conformational flexibility in aqueous solution. In particular, the distribution of ring conformer populations of IdoA2S was determined. The GROMOS96 force field with the SPC/E water potential can predict successfully the dominant skew-boat to chair conformational transition of the IdoA2S monosaccharide in aqueous solution. On the other hand, the GLYCAM06 force field with the TIP3P water potential sampled transitional conformations between the boat and chair forms. Simulations using the GROMOS96 force field showed no pseudorotational equilibrium fluctuations and hence no inter-conversion between the boat and twist boat ring conformers. Calculations of theoretical proton NMR coupling constants showed that the GROMOS96 force field can predict the skew-boat to chair conformational ratio in good agreement with the experiment, whereas GLYCAM06 shows worse agreement. The omega rotamer distribution about the C5–C6 bond was predicted by both force fields to have torsions around 10°, 190°, and 360°. [Copyright &y& Elsevier]

Abstract: Accurate modelling of rotamer equilibria for the primary hydroxyl groups of monosaccharides continues to be a great challenge of computational glycochemistry. The metadynamics technique was applied to study the conformational free energy surfaces of methyl α-d-glucopyranoside and methyl α-d-galactopyranoside, employing the glycam06 force field. For both molecules, seven to eight conformational free-energy minima, differing in the ω (O-5–C-5–C-6–O-6) and χ (C-3–C-4–O-4–HO-4) dihedral angles, were identified in vacuum or in a water environment. The calculated rotamer equilibrium of the primary hydroxyl group is significantly different in vacuum than in water. The major effect of a water environment is the destabilisation of a hydrogen bond between O-4–HO-4 and O-6–HO-6 groups. It was possible to calculate the free-energy differences of individual rotamers with an accuracy of better than 2kJ/mol. The calculated gg, gt and tg rotamer populations in water are in close agreement with experimental measurements, and therefore support the theoretical background of metadynamics. [Copyright &y& Elsevier]

Abstract: The conformational properties of the capsular polysaccharide (CPS) from group B Streptococcus serotype III (GBS III) are derived from 50ns explicitly solvated molecular dynamics simulations of a 25-residue fragment of the CPS. The results from the simulations are shown to be consistent with experimental NMR homo- and heteronuclear J-coupling and NOE data for both the sialylated native CPS and for the chemically desialylated polysaccharide. A helical structure is predicted with a diameter of 29.3Å and a pitch 89.5Å, in which the sialylated side chains are arrayed on the exterior surface of the helix. The results provide an explanation for the observation that CPS antigenicity varies with carbohydrate chain length up to approximately 4 pentasaccharide repeat units. The conformation of the immunodominant region is established and shown to be independent of the presence of sialic acid. The data provide an explanation for the observation that the specificity of the determinant, associated with the major population of antibodies raised upon immunization of rabbits with GBS III, is dependent on the presence of sialic acid. In the sialylated native CPS, the antibody response is largely directed against the immunodominant core of the helix. From simulations of the desialylated CPS, a model emerges which suggests that the minor population of antibodies, whose determinant is not sialic acid dependent, recognizes the same immunodominant region, but that in the disordered CPS this region is not presented in a regular repeating motif. [Copyright &y& Elsevier]

Myelin Oligodendrocyte glycoprotein (MOG) is found to play an important role in providing structural integrity to myelin sheath at the same time it acts as an auto-antigen which might lead to Multiple Sclerosis (MS). What causes this specific property of being an auto-antigen is still not known. Here we present molecular dynamics simulation studies of unfolding and folding of the protein MOG in both the absence and presence of N-glycan in order to understand the role of glycosylation in the stability and flexibility of the protein. The main results from these studies show that the glycosylation increases the stability of the protein MOG and inhibits the complete unfolding of MOG in the SMD. From the folding studies using TMD, it was observed that the glycan helps the protein to attain the near-native folded conformation. However, it was also observed from the direct TMD studies that the pathway of protein folding was enhanced by the trace-back of intermediate states in the presence of glycan. Image 1 • Effect of glycan in Myelin Oligodendrocyte Glycoprotein unfolding and folding. • SMD and TMD were used to study the protein unfolding and folding. • The major results of our study were • Glycosylation maintains the stability of protein MOG. • Glycan enhances the protein intra-molecular interaction and helps in proper folding. [ABSTRACT FROM AUTHOR]