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响应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是由离子通道控制的，离子通道使各种离子能够快速和选择性地穿过细胞膜。离子通道的重要生理作用使它们成为各种生物合成的致命毒素的目标，作为攻击或防御武器。人类基因组有76个基因编码钾通道蛋白，这是最多样化的离子通道组。某些钾离子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。一些心血管和神经系统疾病也可以用针对钾通道的药物治疗。了解钾通道的结构、动力学和药理学对于基础知识和新药设计都很重要。X射线晶体学揭示了几个钾通道在开放和封闭状态下的原子分辨率三维结构。这些结构可用于基于计算机的分子建模研究，旨在预测和可视化通道与各种药物的复合物。本项目将采用功能强大的并行计算机和先进的软件来预测多种药物在几种钾通道中的结合位点，模拟通道蛋白的动力学，预测通道与多种药物的复合物。计算机生成的分子模型将有助于更好地理解钾通道中药物作用的机制。与美国和德国的顶尖科学家合作，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，这可能有助于设计新的有效和选择性的药物。

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.