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首页> 外文期刊>Chemistry: A European journal >Effect of the substituents of the neighboring ring in the conformational equilibrium of iduronate in heparin-like trisaccharides
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Effect of the substituents of the neighboring ring in the conformational equilibrium of iduronate in heparin-like trisaccharides

机译：肝素样三糖中异氰酸酯构象平衡中相邻环取代基的作用

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Based on the structure of the regular heparin, we have prepared a smart library of heparin-like trisaccharides by incorporating some sulfate groups in the sequence α-D-GlcNS- (1-4)-α-L-Ido2S-(1-4)-α-D-GlcN. According to the 3Dstructure of heparin, which features one helix turn every four residues, this fragment corresponds to the minimum binding motif. We have performed a complete NMR study and found that the trisaccharides have a similar 3Dstructure to regular heparin itself, but their spectral properties are such that allow to extract very detailed information about distances and coupling constants as they are isotropic molecules. The characteristic conformational equilibrium of the central iduronate ring has been analyzed combining NMR and molecular dynamics and the populations of the conformers of the central iduronate ring have been calculated. We have found that in those compounds lacking the sulfate group at position6 of the reducing end glucosamine, the population of ~2S_0 of the central iduronate residue is sensitive to the temperature decreasing to 19 % at 278K. On the contrary, the trisaccharides with 6-O-sulfate in the reducing end glucosamine keep the level of population constant with temperature circa 40% of ~2S_0 similar to that observed at room temperature. Another structural feature that has been revealed through this analysis is the larger flexibility of the L-IdoAS- D-GlcN glycosidic linkage, compared with the D-GlcNS-L-IdoA. We propose that this is the point where the heparin chain is bended to form structures far from the regular helix known as kink that have been proposed to play an important role in the specificity of the heparin-protein interaction. The sulfation pattern of the neighboring ring drives the conformational equilibrium of iduronate in heparin trisaccharides. A library of heparin-like trisaccharides incorporating sulfate groups in key positions has been prepared. The conformational equilibrium of the central iduronate ring has been analyzed and the populations were calculated by combining NMR and molecular dynamics (see figure).
机译：根据常规肝素的结构，我们通过在序列α-D-GlcNS-（1-4）-α-L-Ido2S-（1-4）中引入一些硫酸盐基团，制备了一个智能的肝素样三糖文库）-α-D-GlcN。根据肝素的3D结构，其特征是每四个残基旋转一个螺旋角，此片段对应于最小的结合基序。我们已经完成了完整的NMR研究，发现三糖具有与常规肝素本身相似的3D结构，但是它们的光谱特性使得可以提取关于距离和偶联常数的非常详细的信息，因为它们是各向同性的分子。结合NMR和分子动力学分析了中央异丁酸酯环的特征构象平衡，并计算了中央异丁酸酯环的构象体。我们发现，在那些还原端氨基葡萄糖位置6缺少硫酸盐基团的化合物中，中心异戊二酸酯残基的〜2S_0种群对温度在278K下降低至19％敏感。相反，在还原端葡糖胺中带有6-O-硫酸盐的三糖在大约2S_0的40％的温度下保持群体水平不变，这与在室温下观察到的相似。通过该分析揭示的另一结构特征是，与D-GlcNS-L-IdoA相比，L-IdoAS-D-GlcN糖苷键具有更大的灵活性。我们建议在这一点上，肝素链弯曲以形成远离常规螺旋（称为扭结）的结构，该结构被认为在肝素-蛋白质相互作用的特异性中起重要作用。相邻环的硫酸化模式驱动肝素三糖中的异氰酸酯构象平衡。制备了在关键位置结合有硫酸基团的类肝素样三糖文库。已分析了中央异戊二酸酯环的构象平衡，并通过结合NMR和分子动力学计算了总体（见图）。

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