The goal of this research proposal is to pursue our efforts to characterize the fundamental principles governing ion channel function from a detailed atomic and molecular perspective. The KcsA channel provides a fantastic framework for deepening our understanding of the physics of ion permeation and selectivity. This channel also exhibits a gating process involving a conformational change of the selectivity filter similar to the familiar C- type (slow) inactivation. The structures of the open KcsA with its filter in the conductive and inactivated state have now been determined by x-ray crystallography in the Perozo lab, and one can start to unravel the structural and energetic features governing this complex process using advanced computational methods. Concerning voltage gating, the structure of the Kv1.2 channel provides an excellent starting point for designing better atomic models and experiments. Furthermore, there growing body of information about numerous channels, which allows us to address several fundamental issues about permeation concerning the nature of ion diffusion through wide aqueous vestibules and its sensitivity to pore shape and electrostatics. The proposed projects are designed to address fundamental issues about ion permeation, inactivation and gating using a computational and experimental approach. We use a combination of computational (all-atom molecular dynamics simulations, potential of mean force umbrella sampling computations, Poisson-Boltzmann calculations, Brownian dynamics simulations, string method with swarms-of-trajectories) and experimental approaches (x- ray crystallography). The computational efforts are designed to help develop a coherent perspective from the (sometimes conflicting) information from the wide range of structural, biophysical and functional measurements and make experimentally testable predictions. The planned experimental investigations are directly relevant to issues raised by the modeling.

Public Health Relevance

The goal of this research project is to expand our understanding of the function of ion channels at the molecular level using realistic computer simulations and experiments. Malfunction of ion channels have a broad impact on human health, including neurological disorders, epilepsia, heart arrhythmia, immune response, and cellular secretion. The fundamental knowledge gained by the proposed studies is also expected to play an important role in drug discovery and lead optimization.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062342-13
Application #
8318142
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Deatherage, James F
Project Start
2001-01-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$435,049
Indirect Cost
$148,877
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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