Pentameric ligand-gated ion channels (LGICs) are central receptors of electrochemical signaling in cells across evolution, in particular as the major mediator of fast synaptic transmission in the vertebrate nervous system.
In addition to the primary activation by neurotransmitters they are also highly sensitive to allosteric modulators; humankind has used molecules such as ethanol as recreational drugs for four millennia, and ligand-gated ion channels are also the targets of modern pharmaceuticals such as benzodiazepines and anesthetics.
Despite recent structural and functional progress in this field, we still do not understand how channels in the nervous system transiently open before desensitization to a closed channel or why and how channels are regulated by extrinsic factors such as lipids or neurosteroids. Thanks to the project's previous EuroHPC allocation (EHPC-REG-2021R0074), they have performed more than 50 $\mu$s of adaptive sampling-based MD simulations to sample the transition to an open state of gamma-aminobutyric acid (GABA) receptor, a major inhibitory LGICs in our central nervous system.
Capturing this new, physiologically important state provided us with the tremendous opportunity of investigating how different modulatory ligands can potentiate or inhibit the open state. To simulate this process, the project's allocation continues our allocation for the second year.