Does Inter-Residue Hydrogen Bonding in β-(1→4)-Linked Disaccharides Influence Linkage Conformation in Aqueous Solution?
Two disaccharides, methyl β-d-galactopyranosyl-(1→4)-α-d-glucopyranoside (1) and methyl β-d-galactopyranosyl-(1→4)-3-deoxy-α-d-ribo-hexopyranoside (3), were prepared with selective 13C-enrichment to allow measurement of six trans-O-glycosidic J-couplings (2JCOC, 3JCOCH, and 3JCOCC) in each compound. Density functional theory (DFT) was used to parameterize Karplus-like equations that relate these J-couplings to either ϕ or ψ. MA’AT analysis was applied to both linkages to determine mean values of ϕ and ψ in each disaccharide and their associated circular standard deviations (CSDs). Results show that deoxygenation at C3 of 1 has little effect on both the mean values and librational motions of the linkage torsion angles. This finding implies that, if inter-residue hydrogen bonding between O3H and O5′ of 1 is present in aqueous solution and persistent, it plays little if any role in dictating preferred linkage conformation. Hydrogen bonding may lower the energy of the preferred linkage geometry but does not determine it to any appreciable extent. Aqueous 1-μs MD simulation supports this conclusion and also indicates greater conformational flexibility in deoxydisaccharide 3 in terms of sampling several, conformationally distinct, higher-energy conformers in solution. The populations of these latter conformers are low (3–14%) and could not be validated by MA’AT analysis. If the MD model is correct, however, C3 deoxygenation does enable conformational sampling over a wider range of ϕ/ψ values, but linkage conformation in the predominant conformer is essentially identical in both 1 and 3.
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- Award ID(s):
- 2002628
- PAR ID:
- 10496483
- Publisher / Repository:
- ACS Publications
- Date Published:
- Journal Name:
- The Journal of Physical Chemistry B
- Volume:
- 128
- Issue:
- 10
- ISSN:
- 1520-6106
- Page Range / eLocation ID:
- 2317 to 2325
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract MA'AT analysis has been applied to two biologically‐importantO ‐glycosidic linkages in two disaccharides, α‐D‐Galp ‐(1→3)‐β‐D‐Galp OMe (3 ) and β‐D‐Galp ‐(1→3)‐β‐D‐Galp OMe (4 ). Using density functional theory (DFT) to obtain parameterized equations relating a group of trans‐O ‐glycosidic NMR spin‐couplings to eitherphi (ϕ' ) orpsi (ψ' ), and experimental3J COCH,2J COC, and3J COCCspin‐couplings measured in aqueous solution in13C‐labeled isotopomers, probability distributions ofϕ' andψ' in each linkage were determined and compared to those determined by aqueous 1‐μs molecular dynamics (MD) simulation. Good agreement was found between theMA'AT and single‐state MD conformational models of these linkages for the most part, with modest (approximately <15°) differences in the mean values ofϕ' andψ' , although the envelope of allowed angles (encoded in circular standard deviations or CSDs) is consistently larger forϕ' determined fromMA'AT analysis than from MD for both linkages. TheMA'AT model of the α‐Galp ‐(1→3)‐β‐Galp linkage agrees well with those determined previously using conventional NMR methods (3J COCHvalues and/or1H‐1H NOEs), but some discrepancy was observed for the β‐Galp ‐(1→3)‐β‐Galp linkage, which may arise from errors in the conventions used to describe the linkage torsion angles. Statistical analyses of X‐ray crystal structures show ranges ofϕ' andψ' for both linkages that include the mean angles determined fromMA'AT analyses, although both angles adopt a wide range of values in the crystalline state, withϕ' in β‐Galp ‐(1→3)‐β‐Galp linkages showing greater‐than‐expected conformational variability. -
The crystal structure of methyl α-D-mannopyranosyl-(1→3)-2- O -acetyl-β-D-mannopyranoside monohydrate, C 15 H 26 O 12 ·H 2 O, ( II ), has been determined and the structural parameters for its constituent α-D-mannopyranosyl residue compared with those for methyl α-D-mannopyranoside. Mono- O -acetylation appears to promote the crystallization of ( II ), inferred from the difficulty in crystallizing methyl α-D-mannopyranosyl-(1→3)-β-D-mannopyranoside despite repeated attempts. The conformational properties of the O -acetyl side chain in ( II ) are similar to those observed in recent studies of peracetylated mannose-containing oligosaccharides, having a preferred geometry in which the C2—H2 bond eclipses the C=O bond of the acetyl group. The C2—O2 bond in ( II ) elongates by ∼0.02 Å upon O -acetylation. The phi (φ) and psi (ψ) torsion angles that dictate the conformation of the internal O -glycosidic linkage in ( II ) are similar to those determined recently in aqueous solution by NMR spectroscopy for unacetylated ( II ) using the statistical program MA′AT , with a greater disparity found for ψ (Δ = ∼16°) than for φ (Δ = ∼6°).more » « less
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Seven doubly 13 C-labeled isotopomers of methyl β- d -glucopyranoside, methyl β- d -xylopyranoside, methyl β- d -galactopyranoside, methyl β- d -galactopyranosyl-(1→4)-β- d -glucopyranoside and methyl β- d -galactopyranosyl-(1→4)-β- d -xylopyranoside were prepared, crystallized, and studied by single-crystal X-ray crystallography and solid-state 13 C NMR spectroscopy to determine experimentally the dependence of 2 J C1,C3 values in aldopyranosyl rings on the C1–C2–O2–H torsion angle, θ 2 , involving the C2 carbon of the C1–C2–C3 coupling pathway. Using X-ray crystal structures to determine θ 2 in crystalline samples and by selecting compounds that exhibit a relatively wide range of θ 2 values in the crystalline state, 2 J C1,C3 values measured in crystalline samples were plotted against θ 2 and the resulting plot compared to that obtained from density functional theory (DFT) calculations. For θ 2 values ranging from ∼90° to ∼240°, very good agreement was observed between the experimental and theoretical plots, providing strong validation of DFT-calculated spin-coupling dependencies on exocyclic C–O bond conformation involving the central carbon of geminal C–C–C coupling pathways. These findings provide new experimental evidence supporting the use of 2 J CCC values as non-conventional spin-coupling constraints in MA′AT conformational modeling of saccharides in solution, and the use of NMR spin-couplings not involving coupled hydroxyl hydrogens as indirect probes of C–O bond conformation. Solvomorphism was observed in crystalline βGal-(1→4)-βGlcOCH 3 wherein the previously-reported methanol solvate form was found to spontaneously convert to a monohydrate upon air-drying, leading to small but discernible conformational changes in, and a new crystalline form of, this disaccharide.more » « less
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acs.jpcb.3c07448
