Theoretical study of ligand-receptor interactions in potassium channels

大脑、心脏、神经、肌肉和其他器官和组织中的可兴奋细胞会因电信号和化学信号而改变其功能状态。这些重要的生理过程由离子通道控制，离子通道使各种离子能够快速和选择性地渗透到细胞膜上。离子通道的重要生理作用使其成为各种生物合成的致命毒素的攻击或防御武器。人类基因组有76个基因编码钾通道蛋白，钾通道蛋白是最多样化的一组离子通道。一些钾通道基因的突变会导致严重的遗传性疾病，如心律失常。钾通道阻滞剂用于治疗糖尿病、多发性硬化症、牛皮癣和其他自身免疫性疾病。一些心血管和神经疾病也可以通过针对钾通道的药物进行治疗。了解钾通道的结构、动力学和药理学对于基础知识和设计新药很重要。X射线结晶学揭示了几种钾通道在开放和关闭状态下的原子分辨三维结构。这些结构可以用于基于计算机的分子建模研究，目的是预测和可视化通道与各种药物的络合物。在这个项目中，将使用功能强大的并行计算机和复杂的软件来预测各种药物在几个钾通道中的结合部位，模拟通道蛋白的动力学，预测通道与各种药物的络合物。计算机生成的分子模型将有助于更好地理解药物在钾通道中的作用机制。在与美国和德国顶尖科学家的合作下，这些模型将得到实验验证，并用于设计新的实验。这项研究将提供信息，可能有助于设计新的有效和选择性药物。

Excitable cells in the brain, heart, nerves, muscle, and other organs and tissues change their functional state in response to electrical and chemical signals. These important physiological processes are controlled by ion channels, which enable fast and selective permeation of various ions across cell membranes. The crucial physiological role of ion channels has made them targets for deadly toxins synthesized by various organisms as attack or defense weapons. The human genome has 76 genes that encode potassium channel proteins, which are the most diverse group of ion channels. Mutations in some potassium channel genes cause severe inherited disorders such as cardiac arrhythmias. Potassium channel blockers are used for the treatment of diabetes, multiple sclerosis, psoriasis, and other autoimmune diseases. Some cardiovascular and neurological disorders are also treated with drugs, which target potassium channels. Understanding structure, dynamics, and pharmacology of potassium channels is important for basic knowledge and for designing new drugs. X-ray crystallography revealed atomic-resolution three-dimensional structures of several potassium channels in the open and closed states. These structures can be used in computer-based molecular modeling studies aimed to predict and visualize complexes of the channels with various drugs. In this project, powerful parallel computers and sophisticated software will be employed to predict binding sites of various drugs in several potassium channels, to simulate dynamics of the channel proteins and predict complexes of the channels with various drugs. The computer-generated molecular models will help better understand mechanisms of drug action in potassium channels. In collaboration with leading scientists in USA and Germany, the models will be experimentally verified and used to design new experiments. The study will provide information, which may help design new potent and selective drugs.