December 6, Mon 2010
3:30 pm, 1005 Haworth Hall
Dr. Benoit Roux
Department of Biochemistry and Molecular Biology, University of Chicago
Computational study of the ligand-activated Glutamate Receptor
Ligand-gated ion channels mediate information transfer at synapses. The binding of neurotransmitter molecules to the ligand-binding domains (LBDs) of these channels drives the opening of transmembrane pores, allowing the flow of select cations across the cell membrane. The ionotropic glutamate receptor ion channels (iGluRs) mediate excitatory responses at the vast ma jority of synapses in the brain and spinal cord. Our approach is to use equilibrium free energy computations based on detailed atomic models to elucidate the energetics that govern the allosteric mechanisms responsible for iGluR function. Ligand binding has been shown experimentally to proceed in two steps, in which rapid ligand docking is followed by slower domain closure. Understanding the energetics that govern these processes are critical to understanding the fundamental, microscopic basis for receptor activation. We compute the free energy of binding for ligands to iGluR2 using a novel methodology that rigorously accounts for the free energies of both docking and domain closure. The computations advance the understanding of the fundamental mechanisms by which dysfunction in iGluRs give rise to neurological disorders and will aid the design of novel iGluR ligands that can act as therapeutic agents.