A 3D-structural model of unsulfated chondroitin from high-field NMR: 4-sulfation has little effect on backbone conformation

Sattelle, Benedict M.; Shakeri, Javad; Roberts, Ian S.; Almond, Andrew

doi:10.1016/j.carres.2009.11.013

Cited by 51 publications

(121 citation statements)

References 61 publications

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“…Our recent experimental observations 14 led to the hypothesis that two unsulfated chondroitin hexosamine hydroxyl hydrogen atoms (H-O4 and H-O6) are more solvent exposed in this carbohydrate backbone than in the hexosamine 4-epimerized hyaluronan backbone. Temperature coefficient experiments for chondroitin 14 and hyaluronan 66 have also shown the absence of persistent inter-residual hydrogen-bonding involving these atoms. The GLY-CAM06 RDF data illustrated in Figure 6 are consistent with these experimental observations and only GLYCAM06 (and to a lesser extent SCC-DFTB-D) could correctly predict hexosamine H-O4 to GlcA O5 hydrogen bond occupancies in Table 6.…”

Section: Intra-molecular Hydrogen Bonds and Solvent Interactionsmentioning

confidence: 92%

“…Figure 7C illustrates this graphically, further, the presence of non-4 C 1 chair geometries are consistent with the data in Figure 2C and the fact that this method did not reproduce the expected 4 C 1 hexapyranose puckering. Our recent NMR study also concluded that the effect of hexosamine 4-sulfation on the 3D-conformation of unsulfated chondroitin was small 14 ; the b(1?3) u I and w I torsions were found, respectively, to be 118 and 18 more positive in chondroitin-4-sulfate relative to unsulfated chondroitin. Using GLYCAM06, addition of 4-sulfate rendered both glycosidic torsions more positive in CS 2 relative to CN 2 , but to a larger degree than the experimental data (168 and 318 for u I and w I , respectively).…”

Section: Comparison Of Computed and Experimental Disaccharide Conformmentioning

confidence: 92%

“…Our recent NMR study concluded that the b(1?3) w I torsion was 218 more negative in chondroitin than in hyaluronan 14 and that the u I torsion was identical in the two molecules. 8 The GLYCAM06 method predicted w I in the CN 2 model to be 118 more negative than in the HA 2 model (u I was unaltered), which is in close agreement with this experimental data and similar to a previous simulation prediction 15 using the GLYCAM93 59 paramater set.…”

Section: Comparison Of Computed and Experimental Disaccharide Conformmentioning

confidence: 97%

“…Previously, we predicted computationally 15 and subsequently observed experimentally 14 that the hexosamine residue H-O4 and H-O6 atoms (see Fig. 1) are more solvent exposed in the chondroitin carbohydrate backbone than in hyaluronan.…”

Section: Introductionmentioning

confidence: 95%

“…Recent advances in isotopic labeling and material purification have facilitated determination of aqueous 3D-models for representative oligosaccharides in three of the four glycosaminoglycan sub-families (hyaluronan, 8 heparin, [9][10][11] and chondroitin/dermatan [12][13][14] ) by nuclear magnetic resonance (NMR) spectroscopy. Currently, however, only small glycosaminoglycan fragments are amenable to detailed NMR studies due to severe resonance overlap.…”

Section: Introductionmentioning

confidence: 99%

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Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P, PM3‐CARB1/TIP3P, and SCC‐DFTB‐D/TIP3P predictions with experiment

Sattelle¹,

Almond²

2010

J Comput Chem

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The 3D-structure of extracellular matrix glycosaminoglycans is central to function, but is currently poorly understood. Resolving this will provide insight into their heterogeneous biological roles and help to realize their significant therapeutic potential. Glycosaminoglycan chemical isoforms are too numerous to study experimentally and simulation provides a tractable alternative. However, best practice for accurate calculation of glycosaminoglycan 3D-structure within biologically relevant nanosecond timescales is uncertain. Here, we evaluate the ability of three potentials to reproduce experimentally observed glycosaminoglycan monosaccharide puckering, disaccharide 3D-conformation, and characteristic solvent interactions. Temporal dynamics of unsulfated chondroitin, chondroitin-4-sulfate, and hyaluronan β(1→3) disaccharides were simulated within TIP3P explicit solvent unrestrained for 20 ns using the GLYCAM06 force-field and two semi-empirical quantum mechanics methods, PM3-CARB1 and SCC-DFTB-D (both within a hybrid QM/MM formalism). Comparison of calculated and experimental properties (vicinal couplings, nuclear Overhauser enhancements, and glycosidic linkage geometries) showed that the carbohydrate-specific parameterization of PM3-CARB1 imparted quantifiable benefits on monosaccharide puckering and that the SCC-DFTB-D method (including an empirical correction for dispersion) best modeled the effects of hexosamine 4-sulfation. However, paradoxically, the most approximate approach (GLYCAM06/TIP3P) was the best at predicting monosaccharide puckering, 3D-conformation, and solvent interactions. Our data contribute to the debate and emerging consensus on the relative performance of these levels of theory for biological molecules.

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Section: Intra-molecular Hydrogen Bonds and Solvent Interactionsmentioning

confidence: 92%

Section: Comparison Of Computed and Experimental Disaccharide Conformmentioning

confidence: 92%

Section: Comparison Of Computed and Experimental Disaccharide Conformmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P, PM3‐CARB1/TIP3P, and SCC‐DFTB‐D/TIP3P predictions with experiment

Sattelle¹,

Almond²

2010

J Comput Chem

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Glycosaminoglycan Structural Characterization

Langeslay

Beecher

Dinges

et al. 2013

eMagRes

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Glycosaminoglycans (GAGs) are involved in a myriad of biological processes and have the capacity to be implemented as therapeutic agents. These are linear nitrogen-containing glycan polymers that are highly anionic and polydisperse. GAG biological activity is associated with the structure or sequence of regions within the biopolymer, as exemplified by the well-characterized heparin pentasaccharide sequence responsible for its antithrombotic activity. NMR is often the method of choice for the determination of the primary structure of GAG-derived oligosaccharides as well as in the monosaccharide analysis of GAGs such as low-molecular weight heparin drugs. This work describes the methods for determining the structure of intact GAGs and GAG-derived oligosaccharides through chemical shift analysis by one-and twodimensional, homo-and heteronuclear NMR.

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Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic‐resolution molecular simulation

Premnath

Guvench

2017

J Comput Chem

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Proteoglycans (PGs) are covalent conjugates between protein and carbohydrate (glycosaminoglycans). Certain classes of glycosaminoglycans such as chondroitin sulfate/dermatan sulfate and heparan sulfate utilize a specific tetrasaccharide linker for attachment to the protein component: GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser. Toward understanding the conformational preferences of this linker, the present work used all-atom explicit-solvent molecular dynamics (MD) simulations combined with Adaptive Biasing Force (ABF) sampling to determine high-resolution, high-precision conformational free energy maps ΔG(φ, ψ) for each glycosidic linkage between constituent disaccharides, including the variant where GlcA is substituted with IdoA. These linkages are characterized by single, predominant (> 97% occupancy), and broad (45° × 60° for ΔG(φ, ψ) < 1 kcal/mol) free-energy minima, while the Xyl-Ser linkage has two such minima similar in free-energy, and additional flexibility from the Ser sidechain dihedral. Conformational analysis of microsecond-scale standard MD on the complete tetrasaccharide-O-Ser conjugate is consistent with ABF data, suggesting (φ, ψ) probabilities are independent of the linker context, and that the tetrasaccharide acts as a relatively rigid unit whereas significant conformational heterogeneity exists with respect to rotation about bonds connecting Xyl to Ser. © 2017 Wiley Periodicals, Inc.

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A 3D-structural model of unsulfated chondroitin from high-field NMR: 4-sulfation has little effect on backbone conformation

Abstract: Graphical abstract

Cited by 51 publications

References 61 publications

Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P, PM3‐CARB1/TIP3P, and SCC‐DFTB‐D/TIP3P predictions with experiment

Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P, PM3‐CARB1/TIP3P, and SCC‐DFTB‐D/TIP3P predictions with experiment

Glycosaminoglycan Structural Characterization

Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic‐resolution molecular simulation

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