An NMR and molecular modelling study on the solution conformation of Heparan Sulphate: new insights into the relationship between structure and function

A deeper insight into the structural biology of HS is key to understanding its nearuniversal functional role as a co-receptor for growth factors and morphogens. Due to the extreme difficulty in preparing homogeneous HS oligosaccharides for structural and functional studies, traditionally, oligosaccharides derived from the related molecule heparin are used as HS structural models. In this study a number of authentic HS derived hexasaccharides, in addition to heparin derived hexasaccharides, have been purified in sufficient quantity to permit a detailed NMR and molecular modelling based analysis of their three dimensional structure. The primary sequence of one HS derived oligosaccharide has never previously been published. Studies on all oligosaccharides and their chemically de-2-O-sulphated derivatives have revealed additional new insights into the structural influence of sulphate groups. Consistent with previous studies, at the monosaccharide level, sulphation was found to influence iduronate conformational behaviour. However, with the data presented, a number of gaps in the literature have now been filled, and it is now possible for the first time to predict the balance of iduronate conformational equilibria within any HS monosaccharide sequence. Sulphation was also found to influence the overall topology of the oligosaccharide chains themselves. In particular, for the first time NMR data is presented to show that local deviations may occur along the helical axis of each oligosaccharide when it is free in solution. Polyacrylamide gel electrophoresis data and molecular dynamic modelling data are presented to suggest that the rate at which local deviations occur may be influenced by the sulphation pattern contained within a particular oligosaccharide. The functional implications of these and other new structural insights are discussed, and in particular are related to a library of HS derived decasaccharide structures previously tested for biological activity

Author dc:creator

• Murphy, K.J.

• QD Chemistry

Language dc:language

en

Identifier

Murphy, K.J. (2007) An NMR and molecular modelling study on the solution conformation of Heparan Sulphate: new insights into the relationship between structure and function. Doctoral thesis, University of Huddersfield.

OAI identifier oai:identifier

oai:eprints.hud.ac.uk:189