Molecular dynamics studies of AChBP with nicotine and carbamylcholine: the role of water in the binding pocket
Molecular dynamics studies of AChBP with nicotine and carbamylcholine: the role of water in the binding pocket
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DOI：
10.1093/protein/gzm029
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发表时间：
2007-07-01
影响因子：
2.4
通讯作者：
Biggin, Philip C.
中科院分区：
文献类型：
--
作者：
Amiri, Shiva;Sansom, Mark S. P.;Biggin, Philip C.
乙酰胆碱结合蛋白（AChBP）与烟碱乙酰胆碱受体（nAChR）的配体结合结构域和神经递质受体的Cys环家族的其他成员同源。AChBP的高分辨率X射线结构意味着它已被用作了解激动剂和拮抗剂与nAChRs结合的模型。我们在这里提出了一个分子动力学（MD）研究乙酰胆碱结合尼古丁和氨甲酰胆碱。我们的研究结果表明，配体施加刚性的结合口袋残基。模拟还表明，该蛋白质经历呼吸运动相对于五倍轴，运动已被假定为与门控在nAChR。我们分析了结合位点内和周围的水分子的行为，发现它们占据了结合口袋内的五个不同位点。在没有配体的情况下，水占据了这些位点，但是配体的存在增加了在这些位点中发现水分子的可能性。最后，我们展示了如何使用这些沃茨的位置在新的配体的设计，通过比较这些网站的位置与其他最近的结构。
The acetylcholine-binding protein (AChBP) is homologous to the ligand-binding domain of the nicotinic acetylcholine receptor (nAChR) and other members of the Cys-loop family of neurotransmitter receptors. The high-resolution X-ray structures of AChBP mean it has been used as a model from which to understand agonist and antagonist binding to nAChRs. We present here a molecular dynamics (MD) study of AChBP with nicotine and carbamylcholine bound. Our results suggest that the ligand imposes rigidity on the binding pocket residues. The simulations also suggest that the protein undergoes breathing motions with respect to the five-fold axis, a motion that has been postulated to be related to gating in the nAChR. We analyzed the behaviour of the water molecules in and around the binding site and found that they occupied five distinct sites within the binding pocket. Water occupied these sites in the absence of ligand, but the presence of ligand increased the probability that a water molecule would be found in these sites. Finally, we demonstrate how the positions of these waters might be used in the design of new ligands by comparing the positions of these sites with other recent structures.