Jalily Hasani Horia, Ahmed Marawan, Barakat Khaled
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, Alberta, Canada.
J Mol Graph Model. 2017 Nov;78:26-47. doi: 10.1016/j.jmgm.2017.09.019. Epub 2017 Sep 29.
The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (I) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking simulations, encompassing a 4:2 stoichiometry to complete the picture of the channel complex formed by these two proteins. All the protein systems generated through these processes were refined by long Molecular Dynamics simulations. The refined models were analyzed extensively to infer data about the interaction of KCNQ1 channel with its accessory KCNE1 beta subunits.
电压门控的KCNQ1/KCNE1钾离子通道复合物在心脏中形成缓慢延迟整流（I）电流，这在心脏信号传导中起着重要作用。KCNQ1或KCNE1功能丧失和功能获得性突变与长QT综合征、先天性心房颤动和短QT综合征之间的联系，进一步表明了KCNQ1/KCNE1通道功能的重要性。此外，KCNQ1/KCNE1通道是许多非心血管药物的脱靶位点，可导致致命的心脏节律异常。解决和研究KCNQ1/KNCE1通道上述问题的一种方法是使用经过验证的准确模型进行结构研究。在本研究中，我们采用了几种一流的建模方法，为KCNQ1蛋白的开放状态构建了一个准确且与现有实验数据兼容的结构模型。接下来，我们使用数据驱动的蛋白质-蛋白质对接模拟，纳入KCNE1蛋白成分，采用4:2的化学计量比，以完善这两种蛋白质形成的通道复合物的全貌。通过这些过程生成的所有蛋白质系统都经过长时间的分子动力学模拟进行了优化。对优化后的模型进行了广泛分析，以推断有关KCNQ1通道与其辅助KCNE1β亚基相互作用的数据。
