JYVÄSKYLÄ STUDIES IN BIOLOGICAL AND ENVIRONMENTAL SCIENCE Dynamics of the Ligand-Binding Domains of Ionotropic Glutamate Receptors

Postila, Pekka Dynamics of the ligand-binding domains of ionotropic glutamate receptors. Jyväskylä: University of Jyväskylä, 2010, 54 p. (Jyväskylä Studies in Biological and Environmental Science, ISSN 1456-9701; 214) ISBN 978-951-39-4182-6 (PDF), 978-951-39-4081-2 (nid.) Yhteenveto: Ionotrooppisten glutamaattireseptoreiden ligandinsitomisdomeenien dynamiikka. Diss. Ionotropic glutamate receptors (iGluRs) transmit fast neuronal impulses in the synapses of mammalian brain. The binding of neurotransmitter L-glutamate closes the bilobed iGluR cleft of the extracellular ligand-binding domain (LBD). The screw-axis bending of iGluR-LBD in turn opens the tetrameric transmembrane ion channel and influx of cations depolarizes the neuron. The isolated iGluR-LBD referred here as the ligand-binding core (LBC) has been crystallized in complex with various ligands. Full agonists close the iGluR-LBC and, conversely, antagonists block both the receptor cleft closure and ion channel opening. Some partial agonists produce intermediate iGluR-LBC closure in addition to partial activation. In this thesis is demonstrated that receptor cleft closure can be recreated by inserting ligands inside the closed iGluR-LBCs and simulating the complexes with all-atom molecular dynamics (MD) with explicit solvent. During the MD simulations the iGluR cleft either opens (antagonist, partial agonist) or stays closed (full agonist). Accordingly, the closure stages and binding interactions were predicted for novel compounds (e.g. dysiherbaine analogs) without prior crystallographic data. The MD simulations were also used to interpret experimental ligand-binding affinity and receptor subtype specificity data. Although bulky partial agonists and antagonists usually produce full-scale receptor cleft opening in MD simulations, some partial agonists only disrupt the receptor cleft hydrogen bonding. The full agonist-iGluR complex simulations suggest that the stability of cleft closure is receptor subtype-specific. Moreover, the ligand-receptor complex simulations provided a more dynamic view of the iGluR-LBD dynamics than what the crystallographic studies have implied. Because iGluRs contribute to various neuropathologies such as epilepsy and migraine, the receptor family is important target for rational drug discovery.