The role of the peripheral anionic site and cation-π interactions in the ligand penetration of the human AChE gorge
The role of the peripheral anionic site and cation-π interactions in the ligand penetration of the human AChE gorge
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DOI：
10.1021/ja0512780
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发表时间：
2005-06-29
影响因子：
15
通讯作者：
Parrinello, M
中科院分区：
文献类型：
--
作者：
Branduardi, D;Gervasio, FL;Parrinello, M
我们研究了配体（四甲基铵）识别的外围阴离子网站和它的渗透人类AChE峡谷使用原子分子动力学模拟和我们最近开发的metadhesics方法。外围阴离子位点和阳离子-π相互作用在配体入口中的形成的作用被清楚地示出。特别是，与W286 A突变体的模拟显示了该残基在锚定配体在酶的外周阴离子位点和在定位它之前的峡谷入口的基本作用。一旦配体被正确定向，与W86、F295和Y341形成特异性和同步的阳离子-π相互作用，使得能够进行峡谷渗透。最终，配体通过与W86的阳离子-π相互作用稳定在自由能盆中。
We study the ligand (tetramethylammonium) recognition by the peripheral anionic site and its penetration of the human AChE gorge by using atomistic molecular dynamics simulations and our recently developed metadynamics method. The role of both the peripheral anionic site and the formation of cation-pi interactions in the ligand entrance are clearly shown. In particular, a simulation with the W286A mutant shows the fundamental role of this residue in anchoring the ligand at the peripheral anionic site of the enzyme and in positioning it prior to the gorge entrance. Once the ligand is properly oriented, the formation of specific and synchronized cation-pi interactions with W86, F295, and Y341 enables the gorge penetration. Eventually, the ligand is stabilized in a free energy basin by means of cation-pi interactions with W86.