Free Energy Landscapes of Iduronic Acid and Related Monosaccharides
Free Energy Landscapes of Iduronic Acid and Related Monosaccharides
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DOI：
10.1021/ja1054143
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发表时间：
2010-09-29
影响因子：
15
通讯作者：
Almond, Andrew
中科院分区：
文献类型：
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作者：
Sattelle, Benedict M.;Hansen, Steen U.;Almond, Andrew
L-艾杜糖醛酸 (IdoA) 的吡喃糖环是抗凝剂肝素的主要成分，是多个环褶皱的平衡，无法通过实验或计算进行定量。为了解决这个谜团，我们通过广泛的微秒模拟计算了 IdoA 和两种相关单糖的自由能景观。在确定模拟褶皱已达到平衡后，假设得到证实：(a) IdoA C-1(4)-和 C-4(1)-椅构象在微秒时间尺度上交换，(b) C5 差向异构化导致 C-4(1)-椅，(c) IdoA 2-O-硫酸化 (IdoA2S) 稳定 C-1(4) 构象异构体。 IdoA 和 IdoA2S C-1(4) 构象异构体是等能的，经计算其自由能比各自的 C-4(1) 椅构象低 0.9 和 2.6 kcal mol(-1) 。模拟还预测 IdoA S-2(o) 斜交船的人口数量比之前想象的要少。新颖的化学合成和超高场 NMR 支持这些观察结果，但观察到的和预测的 NMR 邻位耦合的轻微差异意味着模拟高估了 IdoA C-4(1)-椅相对于 (1)C(4-) 椅的数量，因为力场误差很小，仅在长时间模拟中才会显现。这些自由能计算推动了计算方法的改进，并为碳水化合物模拟生物材料和药物提供了一条新途径。
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 C-1(4)- and C-4(1)-chair conformations exchange on the microsecond time scale, (b) C5 epimerization leads to a C-4(1)-chair, and (c) IdoA 2-O-sulfation (IdoA2S) stabilizes the C-1(4) conformer. The IdoA and IdoA2S C-1(4) conformers were isoenergetic and computed to be 0.9 and 2.6 kcal mol(-1) lower in free energy than their respective C-4(1)-chair conformations. The simulations also predicted that the IdoA S-2(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 C-4(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.