Interplay between structural rigidity and electrostatic interactions in the ligand binding domain of GluR2.
Interplay between structural rigidity and electrostatic interactions in the ligand binding domain of GluR2.
复制标题
GluR2 配体结合域中结构刚性和静电相互作用之间的相互作用。
DOI：
10.1002/prot.22090
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
Kurnikova,Maria
中科院分区：
文献类型：
--
作者：
Mamonova,Tatyana;Speranskiy,Kirill;Kurnikova,Maria
利用分子动力学(MD)模拟、计算蛋白质修饰和一种确定结构刚性/柔性的新理论方法(第一种算法)，我们研究了谷氨酸受体配体结合域(GluR2 S1S2)的分子结构和动力学如何促进其构象转变。S1S2是一种双叶蛋白质，当结合两叶间裂隙中的激动剂时，会发生裂隙闭合构象转变，因此，这种构象转变的机制可能是铰链型的。然而，在刚性分析中，蛋白质的一个叶被鉴定为单个刚性簇，而另一个叶在结构上是柔性的，与假定的机械铰链机制不一致。相反，我们将裂缝-闭合转变描述为加载和锁定机制。我们发现，当两个交叉裂隙的氢键被破坏时，蛋白质经历了快速的裂隙开启转变。同时，在谷氨酸配体存在下，裂解的动力学行为只受晶体结构中观察到的S652肽键翻转构象的微弱影响。残基E705通过静电作用对闭合构象的稳定起着重要作用。E705-K730盐桥的存在似乎与MD模拟中的裂隙开放转变密切相关。蛋白质2008。©2008 Wiley-Liss，Inc.
Using molecular dynamics (MD) simulations, computational protein modifications, and a novel theoretical methodology that determines structural rigidity/flexibility (the FIRST algorithm), we investigate how molecular structure and dynamics of the glutamate receptor ligand binding domain (GluR2 S1S2) facilitate its conformational transition. S1S2 is a two‐lobe protein, which undergoes a cleft closure conformational transition upon binding an agonist in the cleft between the two lobes; hence it is expected that the mechanism of this conformational transition can be characterized as a hinge‐type. However, in the rigidity analysis one lobe of the protein is identified as a single rigid cluster while the other one is structurally flexible, inconsistent with a presumed mechanical hinge mechanism. Instead, we characterize the cleft‐closing transition as a load and lock mechanism. We find that when two cross‐cleft hydrogen bonds are disrupted the protein undergoes a rapid cleft opening transition. At the same time, the dynamical behavior of the cleft in the presence of the glutamate ligand is only weakly affected by the S652 peptide bond in its flipped conformation observed in the crystal structure. The residue E705 plays significant role in stabilization of the closed conformation via electrostatic interactions. The presence of the E705‐K730 salt bridge seems to correlate strongly withthe cleft opening transition in the MD simulations. Proteins 2008. © 2008 Wiley‐Liss, Inc.