Free energy landscapes of iduronic acid and related monosaccharides.

The pyranose ring of L-iduronic acid (IdoA), a major constituent of the anticoagulant heparin, is an equilibrium of multiple ring puckers that have evaded quantification by experiment or computation. In order to resolve this enigma, we have calculated the free energy landscape of IdoA and two related monosaccharides from extensive microsecond simulations. After establishing that the simulated puckers had reached equilibrium, hypotheses were confirmed that (a) IdoA (1)C(4)- and (4)C(1)-chair conformations exchange on the microsecond time scale, (b) C5 epimerization leads to a (4)C(1)-chair, and (c) IdoA 2-O-sulfation (IdoA2S) stabilizes the (1)C(4) conformer. The IdoA and IdoA2S (1)C(4) conformers were isoenergetic and computed to be 0.9 and 2.6 kcal mol(-1) lower in free energy than their respective (4)C(1)-chair conformations. The simulations also predicted that the IdoA (2)S(O)-skew-boat was less populated than previously thought. Novel chemical synthesis and ultra-high-field NMR supported these observations, but slight discrepancies in observed and predicted NMR vicinal couplings implied that the simulation overestimated the population of the IdoA (4)C(1)-chair with respect to (1)C(4)-chair due to small force field inaccuracies that only manifest in long simulations. These free-energy calculations drive improvements in computational methods and provide a novel route to carbohydrate mimetic biomaterials and pharmaceuticals.

[1]  M J Harvey,et al.  ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale. , 2009, Journal of chemical theory and computation.

[2]  Karl Nicholas Kirschner,et al.  GLYCAM06: A generalizable biomolecular force field. Carbohydrates , 2008, J. Comput. Chem..

[3]  Modesto Orozco,et al.  Recent advances in the study of nucleic acid flexibility by molecular dynamics. , 2008, Current opinion in structural biology.

[4]  M. Petitou,et al.  Conformational flexibility: a new concept for explaining binding and biological properties of iduronic acid-containing glycosaminoglycans. , 1988, Trends in biochemical sciences.

[5]  David P. Anderson,et al.  High-Throughput All-Atom Molecular Dynamics Simulations Using Distributed Computing , 2010, J. Chem. Inf. Model..

[6]  Haiying Liu,et al.  Lessons learned from the contamination of heparin. , 2009, Natural product reports.

[7]  M. Bolognesi,et al.  Function and Structure of Inherently Disordered Proteins This Review Comes from a Themed Issue on Proteins Edited Prediction of Non-folding Proteins and Regions Frequency of Disordered Regions Protein Evolution Partitioning Unstructured Proteins and Regions into Groups Involvement of Inherently Diso , 2022 .

[8]  B. Perly,et al.  Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences. , 1990, Carbohydrate research.

[9]  Thomas J Boltje,et al.  Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research. , 2009, Nature chemistry.

[10]  M. Hricovíni,et al.  Relationship between structure and three-bond proton-proton coupling constants in glycosaminoglycans. , 2007, Carbohydrate research.

[11]  R. Dror,et al.  Long-timescale molecular dynamics simulations of protein structure and function. , 2009, Current opinion in structural biology.

[12]  Cornelis Altona,et al.  Prediction of anti and gauche vicinal proton‐proton coupling constants in carbohydrates: A simple additivity rule for pyranose rings , 1980 .

[13]  Jens Landström,et al.  Glycan flexibility: insights into nanosecond dynamics from a microsecond molecular dynamics simulation explaining an unusual nuclear Overhauser effect. , 2010, Carbohydrate research.

[14]  D. Cremer,et al.  General definition of ring puckering coordinates , 1975 .