bm400067g_si_001.pdf (1.83 MB)
Does Microsecond Sugar Ring Flexing Encode 3D-Shape and Bioactivity in the Heparanome?
journal contribution
posted on 2016-02-19, 12:58 authored by Benedict
M. Sattelle, Javad Shakeri, Andrew AlmondThe biological information encoded
in carbohydrate sequences dwarfs
that of proteins and nucleic acids. Deciphering structure–function
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-α-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.