Theoretical study of ligand-receptor interactions in potassium channels

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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.