Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

21-POS Board 21 Studying Protein-lipid Interactions of a Pentameric Ligand-gated Ion Channel in a Synaptic Membrane as the Basis for Targeting Allosteric Modulation Sites for Drug Design Marc A. Dämgen , Philip C. Biggin. University of Oxford, Oxford, United Kingdom. Pentameric ligand-gated ion channels (pLGICs) mediate fast synaptic transmission and are involved in a range of neurological disorders such as Alzheimer’s, Parkinson’s or epilepsy which makes them pivotal drug targets. However, existing drugs suffer from side effects due to poor subtype selectivity. Targeting allosteric modulator sites has great potential to overcome this problem for the compelling reason that they exhibit more sequence diversity between receptor subtypes than the highly conserved orthosteric sites. Many allosteric sites are located at the lipid- accessible regions of the transmembrane domain. It has therefore been hypothesised that lipids themselves can act as allosteric modulators by interacting with these sites and thus modifying the free energy landscape between functional states. Hence, it is a prerequisite to the understanding of allosteric modulation to firstly characterise the protein-lipid interactions in the natural membrane environment. Although it is known that certain lipid types such as cholesterol, anionic lipids or sphingolipids are crucial for the function of pLGICs, the exact nature of the interactions and how they modulate the receptor remains poorly understood. To shed light into these questions, for the first time we have simulated a pLGIC embedded in a realistic synaptic model membrane containing all lipid types that are crucial for its function. We study the glycine receptor as a representative of the pLGIC class since high quality structures in key functional states are available. Using coarse-grained simulations we can access time scales to obtain a converged lipid distribution, allowing us to characterise the annular lipid shell. Additionally, with all-atom simulations we draw a detailed picture of atomistic protein-lipid interactions with a special focus on allosteric sites, thus elucidating the basis for allosteric modulation.

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