Voltage-gated sodium and calcium channels are transmembrane proteins responsible for the initiation and propagation of action potentials in nerve and muscle cells. Function and modulation of the brain sodium and calcium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in brain neurons - the basis for many aspects of learning, memory and physiological regulation. A major goal in the field of ion channel research has been to understand the structure and function of voltage-gated ion channels. Unfortunately, it is very difficult to obtain structural information about these large membrane proteins using crystallographic and NMR methods. This predicament has led many research groups to rely on less direct methods of molecular biology and membrane biophysics to analyze the structure-function relationships of the voltage-gated ion channels. Recently, major advances have been made in computational methods using de novo structure prediction and a high rate of success has been achieved in predicting verifiable structures. A particularly successful de novo algorithm, called Rosetta, has been developed by a research team led by David Baker at the University of Washington.

The goal of my main project is to develop three-dimensional models of the brain voltage-gated sodium and calcium channels. These models will provide key structural information on the molecular basis of the sodium and calcium channel gating, their modulation by second messenger-activated protein phosphorylation and by peptide neurotoxins, and their interaction with therapeutically useful pore-blocking drugs. The novel features of the models will be experimentally tested using site-directed mutagenesis and electrophysiological techniques. The novel computational tools developed in this project will be generalized for structure prediction of other ion channels. Finally, understanding the brain sodium and calcium channel function and modulation on the structural level will lead to a better understanding of mechanisms of neuromodulation, which in turn will give us profound insights into the fundamental mechanisms underlying learning, memory, emotion and behavior.

I am working closely with Drs. William Catterall's and David Baker's groups. Dr. Catterall's group studying the structure and function of the voltage-gated sodium and calcium channels. Dr. Baker's group works on predicting the three-dimensional protein structure using novel computational methods. My long-term research interests include structure-function studies of ion channels and computational modeling of protein structure, protein-protein, and protein-drug interactions.