Experimental chiroptical verification of linkage flexibility in methyl 3-O-(α-D-mannopyranosyl)-α-D-mannopyranoside

Arndt, Edward R.; Stevens, Eugene S.

doi:10.1002/(sici)1097-0282(199605)38:5<567::aid-bip2>3.0.co;2-q

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…Previous simulations of mannose-containing oligosaccharides have corroborated large conformational mobility at the α-linkages. , A similar picture has been obtained from other experiments. For example, optical rotation studies provided evidence for significant solution linkage flexibility and the population of distinct regions of the linkage (φ,ψ) space, which agrees well with these predictions. Also, in a separate study, NOESY data from a high mannose oligosaccharide were not found to be consistent with a single conformation, indicating a high degree of internal flexibility or the presence of multiple conformations .…”

Section: Resultssupporting

confidence: 65%

Comparison of Aqueous Molecular Dynamics with NMR Relaxation and Residual Dipolar Couplings Favors Internal Motion in a Mannose Oligosaccharide

et al. 2001

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An investigation has been performed to assess how aqueous dynamical simulations of flexible molecules can be compared against NMR data. The methodology compares state-of-the-art NMR data (residual dipolar coupling, NOESY, and (13)C relaxation) to molecular dynamics simulations in water over several nanoseconds. In contrast to many previous applications of residual dipolar coupling in structure investigations of biomolecules, the approach described here uses molecular dynamics simulations to provide a dynamic representation of the molecule. A mannose pentasaccharide, alpha-D-Manp-(1-->3)-alpha-D-Manp-(1-->3)-alpha-D-Manp-(1-->3)-alpha-D-Manp-(1-->2)-D-Manp, was chosen as the model compound for this study. The presence of alpha-linked mannan is common to many glycopeptides, and therefore an understanding of the structure and the dynamics of this molecule is of both chemical and biological importance. This paper sets out to address the following questions. (1) Are the single structures which have been used to interpret residual dipolar couplings a useful representation of this molecule? (2) If dynamic flexibility is included in a representation of the molecule, can relaxation and residual dipolar coupling data then be simultaneously satisfied? (3) Do aqueous molecular dynamics simulations provide a reasonable representation of the dynamics present in the molecule and its interaction with water? In summary, two aqueous molecular dynamics simulations, each of 20 ns, were computed. They were started from two distant conformations and both converged to one flexible ensemble. The measured residual dipolar couplings were in agreement with predictions made by averaging the whole ensemble and from a specific single structure selected from the ensemble. However, the inclusion of internal motion was necessary to rationalize the relaxation data. Therefore, it is proposed that although residual dipolar couplings can be interpreted as a single-structure, this may not be a correct interpretation of molecular conformation in light of other experimental data. Second, the methodology described here shows that the ensembles from aqueous molecular dynamics can be effectively tested against experimental data sets. In the simulation, significant conformational motion was observed at each of the linkages, and no evidence for intramolecular hydrogen bonds at either alpha(1-->2) or alpha(1-->3) linkages was found. This is in contrast to simulations of other linkages, such as beta(1-->4), which are often predicted to maintain intramolecular hydrogen bonds and are coincidentally predicted to have less conformational freedom in solution.

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Section: Resultssupporting

confidence: 65%

Comparison of Aqueous Molecular Dynamics with NMR Relaxation and Residual Dipolar Couplings Favors Internal Motion in a Mannose Oligosaccharide

et al. 2001

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“…Later studies using MD simulations, both in vacuo (Balaji et al, 1994) and including explicit solvent (Homans, 1990), along with other studies using proton relaxation measurements in partially deuterated samples (Hricovíni et al, 1992) all found evidence of internal motion at this linkage, suggesting that both of the previously identified states may be sampled in solution. More recent studies using optical rotation techniques (Stevens, 1994), molecular mechanics modeling (Dowd et al, 1995), and circular dichroism (Arndt and Stevens, 1996) have indeed concluded that states near (80°, Ϫ160°) and (80°, Ϫ80°) are likely to be equally populated in solution. These studies also predicted a small population (ϳ10%) of a state near (160°, Ϫ80°).…”

Section: Comparison To Similar Structuresmentioning

confidence: 99%

Solution Conformations of a Trimannoside from Nuclear Magnetic Resonance and Molecular Dynamics Simulations

Sayers

Prestegard

2000

Biophysical Journal

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N-linked oligosaccharides often act as ligands for receptor proteins in a variety of cell recognition processes. Knowledge of the solution conformations, as well as protein-bound conformations, of these oligosaccharides is required to understand these important interactions. In this paper we present a model for the solution conformations sampled by a simple trimannoside, methyl 3, 6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranoside, which contains two of the most commonly found glycosidic linkages in N-linked oligosaccharides. This model was derived from simulated annealing protocols incorporating distance restraints extracted from NOESY spectra along with torsional restraints computed from three-bond (1)H-(13)C coupling constants measured across the glycosidic bonds. The model was refined in light of unrestrained molecular dynamics simulations conducted in the presence of solvent water. The resulting model depicts a molecule undergoing conformational averaging in solution, adopting four major and two minor conformations. The four major conformations arise from a pair of two-state transitions, one each at the alpha(1-->3) and alpha(1-->6) linkages, whereas the minor conformations result from an additional transition of the alpha(1-->6) linkage. Our data also suggest that the alpha(1-->3) transition is fast and changes the molecular shape slightly, whereas the alpha(1-->6) is much slower and alters the molecular shape dramatically.

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“…Conformation has a major influence on specific rotation angles. ,, Unique low-energy geometries for our fragments were obtained from Monte Carlo conformational searches using the Macromodel program with the MM2* force field. This force field has been found to produce geometries and relative energies of high reliability .…”

Section: Optical Rotation Computationsmentioning

confidence: 99%

Optical Rotation Computation, Total Synthesis, and Stereochemistry Assignment of the Marine Natural Product Pitiamide A

et al. 2000

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We report the joint application of ab initio computations and total synthesis to assign the absolute configuration of a new natural product. The expected specific rotations of the (7S,10R)-and (7R,10R)-isomers of pitiamide A in a CHCl 3 solvent continuum model were determined as +8 and -39, respectively, by CADPAC calculations of the electric-dipole-magnetic-dipole polarizability tensor. Total syntheses of these two stereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinone alkylation, a novel water-accelerated modification of Negishi's zirconocene-catalyzed asymmetric carbometalation as well as an unusual segment condensation via Mitsunobu alkylation of a nosyl-activated amide. The experimental optical rotation measurements confirmed the results of the computational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highlight the considerable structural significance of [R] D data, but, because the optical rotation of the natural product was different from either synthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [R] D data for natural samples.The chlorinated lipid pitiamide A (1) was isolated in 1997 from an extract of a mixed assemblage of Lyngbya majuscula and Microcoleus sp. growing on intact colonies of the hard coral Porites cylindrica on Guam. 1 Pitiamide may act as a feeding deterrent to both vertebrate and invertebrate herbivore species, but the determination of its biological profile has been limited by the lack of availability of sufficient quantities of the natural product.The structure of this unusual vinyl chloride-containing marine metabolite (Figure 1) was determined by 2D NMR spectral analysis and mass spectroscopy, and its [R] D was found to be -10.3 (c 3.0, CHCl 3 , 27°C). 2 The absolute and relative configurations at C(7) and C(10) were not assigned. Pitiamide A is a temperature-and light-sensitive oil, and due to the flexibility of most of its backbone chain, a stereochemical assignment based entirely on NMR spectroscopic methods has not been realized. Elucidation of its relative and absolute stereochemistry by circular dichroism (CD) is also not promising, in particular since the stereocenter at C(10) is not part of a strongly asymmetrically perturbed chromophore absorbing at λ >180 nm (vide infra). Accordingly, calculation of the expected molar rotation of pitiamide A diastereomers and enantiomers represents the most attractive solution to this structural problem, but is most challenging due to the unusually high level of flexibility in the lipid backbone. 3 Recently, we devised a Monte Carlo/ab initio approach to assign the configuration of the complex natural product hennoxazole A from computation of the electric-dipole magneticdipole polarizability tensor of suitable fragment molecules. 3 The computed rotations are Boltzmann-weighted averages of values obtained for individual f...

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Experimental chiroptical verification of linkage flexibility in methyl 3-O-(α-D-mannopyranosyl)-α-D-mannopyranoside

Cited by 6 publications

References 28 publications

Comparison of Aqueous Molecular Dynamics with NMR Relaxation and Residual Dipolar Couplings Favors Internal Motion in a Mannose Oligosaccharide

Comparison of Aqueous Molecular Dynamics with NMR Relaxation and Residual Dipolar Couplings Favors Internal Motion in a Mannose Oligosaccharide

Solution Conformations of a Trimannoside from Nuclear Magnetic Resonance and Molecular Dynamics Simulations

Optical Rotation Computation, Total Synthesis, and Stereochemistry Assignment of the Marine Natural Product Pitiamide A

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