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- Title
Conformations of the iduronate ring in short heparin fragments described by time-averaged distance restrained molecular dynamics.
- Authors
Muñoz-García, Juan Carlos; Corzana, Francisco; de Paz, José L; Angulo, Jesús; Nieto, Pedro M
- Abstract
The polyconformational behavior of l-iduronic acid (L-IdoA2S) in heparin derivatives has been previously analyzed in terms of intra-ring proton–proton vicinal coupling constants (3JHH) through mathematical fit of experimental and theoretical values (Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinay P, Petitou M, Choay J. 1990. Conformer Populations of l-Iduronic Acid Residues in Glycosaminoglycan Sequences. Carbohydr Res. 195:157–167; Muñoz-García JC, López-Prados J, Angulo J, Díaz-Contreras I, Reichardt N, de Paz JL, Martín-Lomas M, Nieto PM. 2012. Effect of the substituents of the neighboring ring in the conformational equilibrium of iduronate in heparin-like trisaccharides. Chemistry. 18:16319–16331.). However, this methodology is subjected to the experimental uncertainties of the J-coupling measurements, the force field deviations and the goodness of the least-squares fit. In the present work, we have used time-averaged distance restrained molecular dynamics (tar-MD) to largely reduce these errors, which enables accurate quantification of the population of conformers, or puckers, of the L-IdoA2S residue, in a set of eight heparin-like trisaccharides following the general sequence d-glucosamine (GlcN)-IdoA-GlcN, directly from the time evolution of the puckering coordinates θ and φ. Thus, by carrying out tar-MD simulations in explicit water, with the exclusive nuclear overhauser enhancement (NOE)-derived distance H2–H5 of the L-IdoA2S 2SO conformer as the unique imposed constraint, we have been able to accurately and easily determine the different extents to which the iduronate ring populates the polar (1C4 chair) and equatorial (2SO skew-boat) areas of the puckering sphere depending on the sulfation pattern of the flanking GlcN residues, under low temperature conditions (278 K). The results indicate that 6-O-sulfation at the reducing-end GlcN residue facilitates the 1C4 to 2SO transitions of the iduronate ring by augmenting the flexibility of the C2–C3 torsion, driving the conformational equilibrium toward a majority of equatorial conformers.
- Subjects
HEPARIN; MOLECULAR dynamics; CONFORMATIONAL analysis; PROTON-proton interactions; GLYCOSAMINOGLYCANS; TRISACCHARIDES
- Publication
Glycobiology, 2013, Vol 23, Issue 11, p1220
- ISSN
0959-6658
- Publication type
Article
- DOI
10.1093/glycob/cwt058