Hyaluronan: The local solution conformation determined by NMR and computer modeling is close to a contracted left-handed 4-fold helix
Hyaluronan: The local solution conformation determined by NMR and computer modeling is close to a contracted left-handed 4-fold helix
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DOI：
10.1016/j.jmb.2006.02.077
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发表时间：
2006-05-19
影响因子：
5.6
通讯作者：
Blundell, CD
中科院分区：
文献类型：
--
作者：
Almond, A;DeAngelis, PL;Blundell, CD
透明质酸(HA)是脊椎动物细胞外基质中普遍存在的一种成分，具有多种生理功能，从填充空间到作为其他大分子的支架。导致这些溶液性质的分子相互作用一直是争论的主题，主要是由于缺乏特定残基的实验数据，还没有出现关于HA在溶液中的三维构象和动力学的共识模型。本文利用分子动力学(MD)模拟和高场核磁共振(NMR)研究了HA的溶液构象。与以前的研究不同，MD模拟包含了显式的水分子和钠离子，而核磁共振实验使用了N-15富集寡糖来获得残基特定的信息。预测得到的平均构象(PDB代码2BVK)几乎是收缩的左旋4倍螺旋；即类似于X射线衍射观察到的玻璃酸钠纤维的构象，但乙酰胺侧链反式为H-2。预测了糖苷键和乙酰氨基侧链在自由溶液中围绕其平均构象分别有13度和18度的标准偏差旋转，并且没有观察到像X-射线纤维衍射精细化描述的固态那样被强烈的分子内氢键稳定。相反，预测了与溶剂分子快速交换的弱而瞬时的氢键。这些预测在数量上与苛刻的残基特定核磁共振数据一致，并对应于HA分子，它作为低聚糖呈棒状，在大分子质量时表现为刚性随机卷曲，与以前的流体动力学观察密切一致。这种对HA溶液构象的新描述与所有现有的实验数据一致，并解释了其粘弹性空间填充性质。这一表示可以作为建模HA和蛋白质之间的关联的基础，这将阐明细胞外基质组装的重要方面。(C)2006爱思唯尔有限公司。保留所有权利。
The polysaccharide hyaluronan (HA) is a ubiquitous component of the vertebrate extracellular matrix with diverse physiological roles from space-filling to acting as a scaffold for other macromolecules. The molecular interactions responsible for these solution properties have been the subject of much debate and, primarily due to the lack of residue-specific experimental data, no consensus model for the three-dimensional conformation nor dynamics of HA in solution has emerged. Here, the solution conformation of HA is investigated using molecular dynamics (MD) simulations and high-field nuclear magnetic resonance (NMR). In contrast to previous studies, MD simulations incorporated explicit water molecules and sodium ions, while NMR experiments utilized N-15-enriched oligosaccharides to allow residue-specific information to be obtained. The resultant average conformation (PDB code 2BVK) is predicted to be almost a contracted left-handed 4-fold helix; i.e. similar to that observed for sodium hyaluronate fibers by X-ray diffraction, but with the acetamido side-chain trans to H-2. The glycosidic linkages and acetamido side-chains are predicted to have standard deviation rotations of 13 degrees and 18 degrees around their mean conformations in free solution, respectively, and are not observed to be stabilized by strong intramolecular hydrogen bonds as X-ray fiber diffraction refinements describe for the solid-state. Rather, weak and transient hydrogen bonds that are in rapid interchange with solvent molecules are predicted. These predictions are quantitatively consistent with demanding residue-specific NMR data and correspond to an HA molecule that is rod-like as an oligosaccharide and behaves as a stiffened random coil at large molecular mass, in close agreement with previous hydrodynamic observations. This new description of the solution conformation of HA is consistent with all available experimental data and accounts for its viscoelastic space-filling properties. This representation can be used as a basis for modeling the association between HA and proteins, which will elucidate important aspects of extracellular matrix assembly. (c) 2006 Elsevier Ltd. All rights reserved.