Does Microsecond Sugar Ring Flexing Encode 3D-Shape and Bioactivity in the Heparanome?

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• 作者：Benedict M. Sattelle ; Javad Shakeri ; Andrew Almond
• 刊名：Biomacromolecules
• 出版年：2013
• 出版时间：April 8, 2013
• 年：2013
• 卷：14
• 期：4
• 页码：1149-1159
• 全文大小：721K
• 年卷期：v.14,no.4(April 8, 2013)
• ISSN：1526-4602

文摘

The biological information encoded in carbohydrate sequences dwarfs that of proteins and nucleic acids. Deciphering structure鈥揻unction relationships in heparin and heparan sulfate (the heparanome) is further compounded by extreme sequence diversity, experimental difficulties, and the computational cost of rigorous modeling. Here we perform unbiased microsecond dynamics simulations of 11 heparanome oligosaccharides (55 microseconds total) to investigate the effect of sequence on 3D-structure and to underpin a coarse-grained model that is consistent with long-time scale experimentally validated atomic motions in water. Pyranose ring flexing (puckering) in 2-O-sulfo-伪-l-iduronic acid, which underlies heparin-mediated anticoagulation, was modulated by polymerization (chain position and adjacent residues), which is supported by previous experiments. Furthermore, in coarse-grained simulations, inclusion of puckering was essential to predict macroscopic hydrodynamic properties of heparan sulfate chains containing hundreds of monosaccharaides. Our structural findings and model enable rational molecular design, and we propose that, in the heparanome, puckering, polymer 3D-shape, and bioactivity are inextricably linked.