title: Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic-resolution molecular simulation.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of New England College of Pharmacy, 716 Stevens Avenue, Portland, Maine, 04103.
authors.forename: Cathy
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Pharmaceutical Sciences, University of New England College of Pharmacy, 716 Stevens Avenue, Portland, Maine, 04103.
authors.forename: Padmavathy
authors.initials: P
authors.lastname: Nandha Premnath
authors.affiliation: Department of Pharmaceutical Sciences, University of New England College of Pharmacy, 716 Stevens Avenue, Portland, Maine, 04103.|Graduate School of Biomedical Science and Engineering, University of Maine, 5775 Stodder Hall, Orono, Maine, 04469.
authors.forename: Olgun
authors.identifier: 0000-0001-5673-7026
authors.initials: O
authors.lastname: Guvench
mesh_terms: D001696:Biomechanical Phenomena; D055592:Biophysical Phenomena; D002809:Chondroitin Sulfates / Q000737:chemistry; D003871:Dermatan Sulfate / Q000031:analogs & derivatives / Q000737:chemistry; D004187:Disaccharides / Q000737:chemistry; D006025:Glycosaminoglycans / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009844:Oligosaccharides / Q000737:chemistry*; D011487:Protein Conformation; D011509:Proteoglycans / Q000737:chemistry*
chemical_list: D004187:Disaccharides; D006025:Glycosaminoglycans; D009844:Oligosaccharides; D011509:Proteoglycans; C069524:dermatan sulfate chondroitin sulfate; D003871:Dermatan Sulfate; D002809:Chondroitin Sulfates
keywords: conformation; glycosaminoglycan; glycosidic linkage; linker; molecular dynamics; proteoglycan; tetrasaccharide