Pentameric ligand-gated ion channels (pLGICs) are important biomolecules that mediate fast synaptic transmission. Their malfunctions are linked to serious neuronal disorders and they are major pharmaceutical targets; in invertebrates, they are involved in insecticide resistance. The complexity of pLGICs and the limited crystallographic information available prevent a detailed understanding of how they function. State-of-the-art computational techniques are therefore crucial to build an accurate picture at the atomic level of the mechanisms which drive the activation of pLGICs, complementing the available experimental data. We have used a series of simulation methods, including homology modelling, ligand–protein docking, density functional theory, molecular dynamics and metadynamics, a powerful scheme for accelerating rare events, with the guidance of mutagenesis electrophysiology experiments, to explore ligand-binding mechanisms, the effects of mutations and the potential role of a proline molecular switch for the gating of the ion channels. Results for the insect RDL receptor, the GABAC receptor, the 5-HT3 receptor and the nicotinic acetylcholine receptor will be reviewed.
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April 2015
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Conference Article|
April 07 2015
Elucidating ligand binding and channel gating mechanisms in pentameric ligand-gated ion channels by atomistic simulations
Federico Comitani;
Federico Comitani
*Physics Department, King's College London, Strand, London WC2R 2LS, U.K.
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Claudio Melis;
Claudio Melis
†Dipartimento di Fisica, Università degli Studi di Cagliari, Complesso Universitario di Monserrato, S.P. Monserrato-Sestu Km 0,700, I-09042 Monserrato (CA), Italy
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Carla Molteni
Carla Molteni
1
*Physics Department, King's College London, Strand, London WC2R 2LS, U.K.
1To whom correspondence should be addressed (emailcarla.molteni@kcl.ac.uk).
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Publisher: Portland Press Ltd
Received:
September 22 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem Soc Trans (2015) 43 (2): 151–156.
Article history
Received:
September 22 2014
Citation
Federico Comitani, Claudio Melis, Carla Molteni; Elucidating ligand binding and channel gating mechanisms in pentameric ligand-gated ion channels by atomistic simulations. Biochem Soc Trans 1 April 2015; 43 (2): 151–156. doi: https://doi.org/10.1042/BST20140259
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