Reconciling solvent effects on rotamer populations in carbohydrates - A joint MD and NMR analysis

The rotational preferences of the hydroxymethyl group in pyranosides is known to depend on the local environment, whether in solid, solution, or gas phase. By combining molecular dynamics (MD) simulations with NMR spectroscopy the rotational preferences for the ω angle in methyl 2,3-di-O-methyl-α-D-glucopyranoside (3) and methyl 2,3-di-O-methyl-α-D-galactopyranoside (6) in a variety of solvents, with polarities ranging from 80 to 2.3 D have been determined. The effects of solvent polarity on intramolecular hydrogen bonding have been identified and quantified. In water, the internal hydrogen bonding networks are disrupted by competition with hydrogen bonds to the solvent. When the internal hydrogen bonds are differentially disrupted, the rotamer populations associated with the ω angle may be altered. In the case of 3 in water, the preferential disruption of the interaction between HO6 and O4 destabilizes the tg rotamer, leading to the observed preference for gauche rotamers. Without the hydrogen bond enhancement offered by a low polarity environment, both 3 and 6 display rotamer populations that are consistent with expectations based on the minimization of repulsive intramolecular oxygen–oxygen interactions. In a low polarity environment, HO6 prefers to interact with O4, however, in water these interactions are markedly weakened, indicating that HO6 acts as a hydrogen bond donor to water

Molecular simulations of carbohydrates and protein–carbohydrate interactions: motivation, issues and prospects

The characterization of the 3D structure of oligosaccharides, their conjugates and analogs is particularly challenging for traditional experimental methods. Molecular simulation methods provide a basis for interpreting sparse experimental data and for independently predicting conformational and dynamic properties of glycans. Here, we summarize and analyze the issues associated with modeling carbohydrates, with a detailed discussion of four of the most recently developed carbohydrate force fields, reviewed in terms of applicability to natural glycans, carbohydrate–protein complexes and the emerging area of glycomimetic drugs. In addition, we discuss prospectives and new applications of carbohydrate modeling in drug discovery