Is N-acetyl-D-glucosamine a rigid 4C1 chair?
Is N-acetyl-D-glucosamine a rigid 4C1 chair?
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DOI：
10.1093/glycob/cwr101
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发表时间：
2011-12
期刊：
影响因子：
4.3
通讯作者：
Almond A
中科院分区：
文献类型：
--
作者：
Sattelle BM;Almond A
了解微秒时间尺度的动力学对于建立糖的三维（3D）结构-活性关系至关重要，但在实验和模拟中一直很难解决。因此，可以说是糖生物学中最重要的化学支架，N-乙酰基-D-葡萄糖胺（GlcNAc），是否偏离了刚性4C 1椅子是未知的。在这里，构象的人口和交换动力学进行了量化，从最长的水溶性碳水化合物模拟到目前为止（0.2毫秒总）的GlcNAc，四个衍生物硫酸乙酰肝素和他们的甲基糖苷。未修饰的GlcNAc需要3-5 μs才能达到构象平衡，其中包括一个亚稳态的4C 1椅子，以0.8 μs−1的预测正向速率进行4C 1参与1C 4跃迁，平均1C 4椅子寿命为3 ns。这些预测与高分辨率晶体学和核磁共振相一致，但不符合GlcNAc是刚性4C 1椅子的假设，该假设是从先前的实验分析和非水模型得出的。甲基糖苷的正向速率较慢（0.3 μs−1），4C 1构象更稳定（0.2 kcal mol−1），这表明关键的3D中间体（特别是2SO，1 S5和B2，5）能量增加，水被认为是主要原因。磺化（N-，3-O和6-O）显着增强这种效果，通过阻断伪旋转，但没有改变羟基或羟甲基的旋转偏好。因此，我们建议，GlcNAc进行起皱交换，这是依赖于聚合和磺基取代基。我们的分析，和3D模型的平衡GlcNAc构象在水中，可以用作字典数据，并提出了新的机会，合理地修改起皱和碳水化合物的生物活性，从提高作物产量，以改善疾病的不同应用。
Understanding microsecond-timescale dynamics is crucial to establish three-dimensional (3D) structure–activity relationships in sugars but has been intractable to experiments and simulations. As a consequence, whether arguably the most important chemical scaffold in glycobiology, N-acetyl-d-glucosamine (GlcNAc), deviates from a rigid 4C1 chair is unknown. Here, conformer populations and exchange kinetics were quantified from the longest aqueous carbohydrate simulations to date (0.2 ms total) of GlcNAc, four derivatives from heparan sulfate and their methylglycosides. Unmodified GlcNAc took 3–5 μs to reach a conformational equilibrium, which comprised a metastable 4C1 chair that underwent 4C1 ↔ 1C4 transitions at a predicted forward rate of 0.8 μs−1 with an average 1C4-chair lifetime of 3 ns. These predictions agree with high-resolution crystallography and nuclear magnetic resonance but not with the hypothesis that GlcNAc is a rigid 4C1 chair, concluded from previous experimental analyses and non-aqueous modeling. The methylglycoside was calculated to have a slower forward rate (0.3 μs−1) and a more stable 4C1 conformer (0.2 kcal mol−1), suggesting that pivotal 3D intermediates (particularly 2SO, 1S5 and B2,5) increased in energy, and water was implicated as a major cause. Sulfonation (N-, 3-O and 6-O) significantly augmented this effect by blocking pseudorotation, but did not alter the rotational preferences of hydroyxl or hydroxymethyl groups. We therefore propose that GlcNAc undergoes puckering exchange that is dependent on polymerization and sulfo substituents. Our analyses, and 3D model of the equilibrium GlcNAc conformer in water, can be used as dictionary data and present new opportunities to rationally modify puckering and carbohydrate bioactivity, with diverse applications from improving crop yields to disease amelioration.
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影响因子：
3.1
作者：
DOWD, MK;FRENCH, AD;REILLY, PJ
通讯作者：
REILLY, PJ
影响因子：
5.6
作者：
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通讯作者：
De Fabritiis, G.
影响因子：
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作者：
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Almond, Andrew
影响因子：
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作者：
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通讯作者：
Hsieh-Wilson, Linda C.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A