Free Energy Landscapes of Iduronic Acid and Related Monosaccharides

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• 作者：Benedict M. Sattelle ; Steen U. Hansen ; John Gardiner ; Andrew Almond
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：September 29, 2010
• 年：2010
• 卷：132
• 期：38
• 页码：13132-13134
• 全文大小：145K
• 年卷期：v.132,no.38(September 29, 2010)
• ISSN：1520-5126

文摘

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 ¹C₄- and ⁴C₁-chair conformations exchange on the microsecond time scale, (b) C5 epimerization leads to a ⁴C₁-chair, and (c) IdoA 2-O-sulfation (IdoA2S) stabilizes the ¹C₄ conformer. The IdoA and IdoA2S ¹C₄ conformers were isoenergetic and computed to be 0.9 and 2.6 kcal mol⁻¹ lower in free energy than their respective ⁴C₁-chair conformations. The simulations also predicted that the IdoA ²S_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 ⁴C₁-chair with respect to ¹C₄-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.