The conformational flexibility of methyl α-cellobioside in water and dimethyl sulfoxide solutions was
investigated by 1D 1H,H T-ROESY experiments. In combination with molecular dynamics simulations,
effective proton−proton distances could be derived using experimentally determined cross-relaxation rates.
An anti-ψ-conformational state was present in both solvents confirming a previous flexibility hypothesis at
this torsion angle. In water solution, an anti-φ-conformational state was also detected and quantified. These
results show that already at the disaccharide level a large flexibility is present at the glycosidic linkage. In
addition to the syn-conformation which is present to ∼93% for the title compound in water solution, the
minor anti-φ- and anti-ψ-conformational states are populated to ∼2% and ∼5%, respectively.
The three-dimensional structure of a cyclic enterobacterial common antigen (ECA) having four trisaccharide repeating units has been investigated by NMR spectroscopy and molecular dynamics simulations. Three different NMR parameters were determined: (a) (1)H,(1)H cross-relaxation rates from NOE experiments were used for determination of proton-proton distances; (b) trans-glycosidic (3)J(C,H) scalar coupling constants analyzed via a Karplus-type relationship provided information on torsion angles; and (c) (1)H,(13)C one-bond dipolar couplings obtained in a dilute liquid-crystalline medium were interpreted in terms of the orientational order and molecular conformations. The molecular dynamics simulations of the dodecasaccharide were performed with explicit water and counterions, which are important factors that strongly influence molecular conformation. Subsequently, the results from computer simulation were used to generate a three-dimensional structure of the cyclic ECA which is consistent with the experimental NMR parameters.
The tetrasaccharide lacto-N-neotetraose, β-D-Galp-(1f4)-β-D-GlcpNAc-(1f3)-β-D-Galp-(1f4)-D-Glcp, was investigated by measurements of residual dipolar couplings in two lyotropic liquid crystalline media: (i) prepared from mixtures of dimyristoyl phosphatidylcholine and dihexanoyl phosphatidylcholine in water, and (ii) a ternary system consisting of cetylpyridinium chloride/n-hexanol/brine (200 mM NaCl in water). Computer simulations, both Monte Carlo and molecular dynamics, were performed where different force fields were employed. The molecular structures generated were used in the analysis of the experimental dipolar C-H couplings. This analysis indicated that in addition to different orientational tensors, a small conformational difference may be present for the oligosaccharide in the two media. This interpretation emerged from a procedure where the effect of rotation around one central glycosidic torsion angle on dipolar couplings was investigated. Thus, the approach based on measurement of dipolar couplings is a sensitive tool for investigation of molecular conformation.
The trisaccharide beta-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe has been investigated by molecular dynamics (MD) simulations and NMR experiments in water. 13C spin-lattice (T1) and spin-spin (T2) relaxation times, together with 1H,13C NOE data were measured at two magnetic field strengths (9.4 and 14.1 T) in a 277 K D2O solution. Relaxation data interpreted by means of the model-free formalism revealed a rigid (S2 approximately 0.9) oligosaccharide tumbling in solution. 1H,1H Cross-relaxation rates were determined at 600 MHz by 1D DPFGSE NOESY and T-ROESY experiments, which provided high quality data and subsequently proton-proton distances within the trisaccharide. The presence of anti conformers at both torsions of a glycosidic linkage is demonstrated for the first time. MD simulations were carried out to facilitate analysis of the NOE data. In total, 15 simulations-starting from five different conformational states--were performed, with production runs of up to 10 ns, resulting in 83 ns of oligosaccharide dynamics in water. anti Conformers were populated to different degrees in the simulations, especially at the phi2 torsion angle. By combining the results from the NOE experiments and the MD simulations, the anti conformers at the (1-->2)-linkage were quantified as 7% anti-phi2 and 2% anti-psi2, revealing a highly flexible trisaccharide in which large conformational changes occur. From the MD simulations, interresidue hydrogen bonding, from HO2" to O2 or O3, was significantly populated (approximately 40%) in both of the anti conformational states. The contentious issue over rigidity versus flexibility in oligosaccharides has thus been thoroughly examined, showing that the dynamics should be taken into account for a relevant description of the molecular system.
A novel protocol for protein homology modeling is described, in which uncertainty in protein structure is resolved by applying the criterion that the protein must bind to a complementary ligand. A diverse library of protein models is created and then screened by docking with ligands of known conformation. The more accurate protein models form higher-quality docked complexes, and the quality of the fit is used to select the best models. The effectiveness of this technique with both natural and unnatural ligands is demonstrated by modeling the Fv fragment of an antibody and comparing the results to known crystal structures.
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