OPEN BACK DOOR IN A MOLECULAR-DYNAMICS SIMULATION OF ACETYLCHOLINESTERASE
OPEN BACK DOOR IN A MOLECULAR-DYNAMICS SIMULATION OF ACETYLCHOLINESTERASE
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DOI：
10.1126/science.8122110
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发表时间：
1994-03-04
期刊：
影响因子：
56.9
通讯作者：
SUSSMAN, JL
中科院分区：
文献类型：
--
作者：
GILSON, MK;STRAATSMA, TP;SUSSMAN, JL
乙酰胆碱酯酶产生强大的静电场，可以将阳离子底物乙酰胆碱吸引到活性位点。然而，狭长的活性位点峡谷似乎与酶的高催化速率不一致。水中乙酰胆碱酯酶的分子动力学模拟揭示了一个短通道的瞬时打开，该通道大到足以让水分子通过，穿过色氨酸 84 附近活性位点的薄壁。该模拟表明，除了晶体结构揭示的入口之外，底物、产物或溶剂还可以通过这个“后门”移动。静电计算显示后门处有很强的场，其方向是吸引底物和反应产物胆碱并排斥另一种反应产物乙酸盐。对开放后门构象的分析表明，存在一种可以密封后门的突变，从而检验了这种酶的热运动可能打开通往其活性位点的多种途径的假设。
The enzyme acetylcholinesterase generates a strong electrostatic field that can attract the cationic substrate acetylcholine to the active site. However, the long and narrow active site gorge seems inconsistent with the enzyme's high catalytic rate. A molecular dynamics simulation of acetylcholinesterase in water reveals the transient opening of a short channel, large enough to pass a water molecule, through a thin wall of the active site near tryptophan-84. This simulation suggests that substrate, products, or solvent could move through this ''back door,'' in addition to the entrance revealed by the crystallographic structure. Electrostatic calculations show a strong field at the back door, oriented to attract the substrate and the reaction product choline and to repel the other reaction product, acetate. Analysis of the open back door conformation suggests a mutation that could seal the back door and thus test the hypothesis that thermal motion of this enzyme may open multiple routes of access to its active site.