Abstract
Glycosaminoglycans (GAGs) are the linear carbohydrate components of proteoglycans (PGs) and are key mediators in the bioactivity of PGs in animal tissue. GAGs are heterogeneous, conformationally complex, and polydisperse, containing up to 200 monosaccharide units. These complexities make studying GAG conformation a challenge for existing experimental and computational methods. We previously described an algorithm we developed that applies conformational parameters (i.e., all bond lengths, bond angles, and dihedral angles) from molecular dynamics (MD) simulations of nonsulfated chondroitin GAG 20-mers to construct 3-D atomic-resolution models of nonsulfated chondroitin GAGs of arbitrary length. In the current study, we applied our algorithm to other GAGs, including hyaluronan and nonsulfated forms of dermatan, keratan, and heparan and expanded our database of MD-generated GAG conformations. Here, we show that individual glycosidic linkages and monosaccharide rings in 10- and 20-mers of hyaluronan and nonsulfated dermatan, keratan, and heparan behave randomly and independently in MD simulation and, therefore, using a database of MD-generated 20-mer conformations, that our algorithm can construct conformational ensembles of 10- and 20-mers of various GAG types that accurately represent the backbone flexibility seen in MD simulations. Furthermore, our algorithm efficiently constructs conformational ensembles of GAG 200-mers that we would reasonably expect from MD simulations.
Highlights
Proteoglycans (PGs) are a diverse group of proteins in the extracellular matrix (ECM), as well as on and within cells in animal tissue
Hyaluronan can predict disease outcome and is used as a treatment for osteoarthritis [18,19]; deficiency of dermatan sulfate has been linked to Ehlers-Danlos syndrome, so screening of dermatan sulfate in urine may present a method of diagnosis [20,21]; reduced cerebral cell keratan sulfate levels have been implicated in Alzheimer’s disease [22]; and heparan sulfate has been shown to induce septic shock [23,24]
Crystal structures of hyaluronan oligosaccharides in complexes with proteins [92,93,94,95] were examined and we found that most glycosidic linkage conformations were similar to the most energetically-favorable conformations observed in molecular dynamics (MD) simulation, with the exception of one GlcAβ1-3GlcNAc linkage conformation with −φ, +ψ dihedrals, which was seen in a hyaluronan hexasaccharide in complex with hyaluronidase [94]
Summary
Proteoglycans (PGs) are a diverse group of proteins in the extracellular matrix (ECM), as well as on and within cells in animal tissue. PGs play key roles in signal transduction [1,2], tissue morphogenesis [3,4,5,6,7], and matrix assembly [7,8,9,10] by binding growth factors [3,4,5,6,7,11,12,13,14,15,16,17], enzymes [7,17], membrane receptors [17], and ECM molecules [2,7,17] Many of these functions are mediated by glycosaminoglycans (GAGs), which are linear, highly negatively-charged, and structurally diverse carbohydrate chains covalently-linked to PGs. GAGs can form covalent and noncovalent complexes with proteins or inhibit complex formation with other biomolecules. Hyaluronan can predict disease outcome and is used as a treatment for osteoarthritis [18,19]; deficiency of dermatan sulfate has been linked to Ehlers-Danlos syndrome, so screening of dermatan sulfate in urine may present a method of diagnosis [20,21]; reduced cerebral cell keratan sulfate levels have been implicated in Alzheimer’s disease [22]; and heparan sulfate has been shown to induce septic shock [23,24]
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