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首页> 外文期刊>Journal of theoretical & computational chemistry >COMPUTER SIMULATIONS OF THE INTERACTION OFCIGUATOXIN 3C, BREVENAL AND ent-BREVENAL LADDERPOLYETHERS WITH A HOMOLOGY MODEL OF THEVOLTAGE-GATED Kv1.5 POTASSIUM CHANNEL
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COMPUTER SIMULATIONS OF THE INTERACTION OFCIGUATOXIN 3C, BREVENAL AND ent-BREVENAL LADDERPOLYETHERS WITH A HOMOLOGY MODEL OF THEVOLTAGE-GATED Kv1.5 POTASSIUM CHANNEL

机译：带有门控的Kv1.5钾通道的同源性模型的环瓜辛3C，肠道和肠间脂肪聚酯相互作用的计算机模拟

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摘要

The interaction of ladder polyethers of marine origin, like ciguatoxin 3C and brevenal,as well as hypothetic ent-brevenal, with the human voltage-gated Kv1.5 potassium ionchannel is investigated in this work using homology modeling, automated docking, andenergy scoring from molecular dynamics (MD) simulations. A 3D homology model ofthe pore region of the Kv1.5 channel, previously developed from the 2.9 A resolutioncrystal structure of the mammalian Kv1.2 channel — which has a very similar poresequence — is used here. While ciguatoxin 3C did not enter the pore, both brevenaland ent-brevenal were found into the pore, the latter one with the best score. Bindingis attended by notable strain in the ligands, and the corresponding energy increase wasevaluated for ent-brevenal by self consistent field (SCF) and density functional theory(DFT) procedures. Egress of ent-brevenal from the pore, as a microscopical reversal ofthe ingress, was investigated by a smart form of biased MD simulations. While this studyindicates ample room and attractive interactions for both brevenal and its enantiomerinto the pore, whether these molecules will be found to inhibit voltage-gated potassiumion currents depends upon the barriers in the real system to access the pore, with theirthermodynamic and kinetic requirements.
机译：在这项工作中，使用同源性建模，自动对接和从分子进行能量评分，研究了海洋起源的梯形聚醚（如雪茄毒素3C和brevenal）以及假想的ent-brevenal与人电压门控Kv1.5钾离子通道的相互作用。动力学（MD）模拟。这里使用的是Kv1.5通道孔区域的3D同源性模型，该模型先前是从2.9 K分辨率的哺乳动物Kv1.2通道的分辨率晶体结构开发的，该结构具有非常相似的孔序列。尽管雪茄毒素3C并未进入毛孔，但两个brevenaland ent-brevenal均被发现进入毛孔，后者得分最高。结合过程中，配体中存在明显的应变，并通过自洽场（SCF）和密度泛函理论（DFT）程序评估了相应的能量增加。通过细致的MD模拟，研究了入口肠的出口，作为入口的微观逆转。尽管这项研究表明布氏和其对映异构体在孔中有足够的空间和有吸引力的相互作用，但是否会发现这些分子抑制电压门控的钾离子电流取决于实际系统中进入孔的障碍及其热力学和动力学要求。

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