Zhang Deqiang, Gullingsrud Justin, McCammon J Andrew
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA 92093-0365, USA.
J Am Chem Soc. 2006 Mar 8;128(9):3019-26. doi: 10.1021/ja057292u.
The nicotinic acetylcholine receptor is a prototype ligand-gated ion channel that mediates signal transduction in the neuromuscular junctions and other cholinergic synapses. The molecular basis for the energetics of ligand binding and unbinding is critical to our understanding of the pharmacology of this class of receptors. Here, we used steered molecular dynamics to investigate the unbinding of acetylcholine from the ligand-binding domain of human alpha7 nicotinic acetylcholine receptor along four different predetermined pathways. Pulling forces were found to correlate well with interactions between acetylcholine and residues in the binding site during the unbinding process. From multiple trajectories along these unbinding pathways, we calculated the potentials of mean force for acetylcholine unbinding. Four available methods based on Jarzynski's equality were used and compared for their efficiencies. The most probable pathway was identified to be along a direction approximately parallel to the membrane. The derived binding energy for acetylcholine was in good agreement with that derived from the experimental binding constant for acetylcholine binding protein, but significantly higher than that for the complete human alpha7 nicotinic acetylcholine receptor. In addition, it is likely that several intermediate states exist along the unbinding pathways.
烟碱型乙酰胆碱受体是一种典型的配体门控离子通道，介导神经肌肉接头和其他胆碱能突触中的信号转导。配体结合和解离的能量学分子基础对于我们理解这类受体的药理学至关重要。在此，我们使用引导分子动力学沿着四条不同的预定路径研究乙酰胆碱从人α7烟碱型乙酰胆碱受体的配体结合结构域的解离。在解离过程中，发现拉力与乙酰胆碱和结合位点中残基之间的相互作用密切相关。沿着这些解离路径的多个轨迹，我们计算了乙酰胆碱解离的平均力势。使用并比较了基于雅尔津斯基等式的四种可用方法的效率。确定最可能的路径是沿着大致平行于膜的方向。推导出的乙酰胆碱结合能与从乙酰胆碱结合蛋白的实验结合常数得出的结果高度一致，但显著高于完整的人α7烟碱型乙酰胆碱受体的结合能。此外，沿着解离路径可能存在几个中间状态。
