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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Deatherage, James F
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University of Chicago
Schools of Medicine
United States
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Weingarth, Markus; van der Cruijsen, Elwin A W; Ostmeyer, Jared et al. (2014) Quantitative analysis of the water occupancy around the selectivity filter of a K+ channel in different gating modes. J Am Chem Soc 136:2000-7
Gumbart, James C; Beeby, Morgan; Jensen, Grant J et al. (2014) Escherichia coli peptidoglycan structure and mechanics as predicted by atomic-scale simulations. PLoS Comput Biol 10:e1003475
Li, Qufei; Wanderling, Sherry; Paduch, Marcin et al. (2014) Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. Nat Struct Mol Biol 21:244-52
Dhakshnamoorthy, Balasundaresan; Ziervogel, Brigitte K; Blachowicz, Lydia et al. (2013) A structural study of ion permeation in OmpF porin from anomalous X-ray diffraction and molecular dynamics simulations. J Am Chem Soc 135:16561-8
Lau, Albert Y; Salazar, Hector; Blachowicz, Lydia et al. (2013) A conformational intermediate in glutamate receptor activation. Neuron 79:492-503
Khalili-Araghi, Fatemeh; Ziervogel, Brigitte; Gumbart, James C et al. (2013) Molecular dynamics simulations of membrane proteins under asymmetric ionic concentrations. J Gen Physiol 142:465-75
Beeby, Morgan; Gumbart, James C; Roux, Benoit et al. (2013) Architecture and assembly of the Gram-positive cell wall. Mol Microbiol 88:664-72
Rowley, Christopher N; Roux, Benoit (2013) A computational study of barium blockades in the KcsA potassium channel based on multi-ion potential of mean force calculations and free energy perturbation. J Gen Physiol 142:451-63
Ziervogel, Brigitte K; Roux, Benoit (2013) The binding of antibiotics in OmpF porin. Structure 21:76-87
Ostmeyer, Jared; Chakrapani, Sudha; Pan, Albert C et al. (2013) Recovery from slow inactivation in K+ channels is controlled by water molecules. Nature 501:121-4

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