Abstract
Pentameric ligand gated ion channels (pLGICs) are important neuroreceptors, embedded in neuronal membranes, where they mediate fast synaptic communication. They are involved in many neurological disorders and are targets sites for drugs. However, due to their complexity and the limited structural information available, how they function at the molecular level is still far from being fully understood. In this PhD project we will focus on a specific pLGIC, the glycine receptor, with the goal to understand how the binding of glycine activates the receptor and opens its channel.. We will achieve this by a unique combination of innovative computational techniques and single channel experiments.
References
1. Federico Comitani, Netta Cohen, Dominic Botten, Jamie A. Ashby, Sarah C.R. Lummis and Carla Molteni, “Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models”, J. Comput. Aided Mol. Des., 28, 35-48 (2014). DOI: 10.1007/s10822-013-9704-0
2. Federico Comitani, Claudio Melis and Carla Molteni, “Elucidating Ligand Binding and Channel Gating Mechanisms in Pentameric Ligand-Gated Ion Channels by atomistic simulations”, Biochem. Soc. Trans. 43, 151-156 (2015). DOI: 10.1042/BST20140259
3. Federico Comitani, Vittorio Limongelli and Carla Molteni, “The Free Energy Landscape of GABA Binding to a Pentaretic Ligand-gated Ion Channel and its Disruption by Mutations”, J. Chem. Theory Comput. 12, 3398-3406 (2016). DOI: 10.1021/acs.jctc.6b00303
4. Remigijus Lape, David Colquhoun and Lucia Sivilotti, “On the nature of partial agonism in the nicotinic superfamily” Nature 454, 722-727 (2008). doi: 10.1038/nature07139
5. Michael Epstein, Ben Calderhead, Mark Girolami and Lucia Sivilotti, “Bayesian statistical inference in ion-channel models with exact missed event correction” Biophysical J, 111,333-48 (2016). doi: 10.1016/j.bpj.2016.04.053