Dynamics and Interplay of the Binding Pockets in the Glycine Receptor

The glycine receptor, a pentameric ligand-gated ion channel, plays a vital role in inhibitory neurotransmission, reflexes and neuronal excitability. It is crucial to maintaining the balance and responsiveness of the nervous system to sensory input. The binding of ligands, in this case glycines, in the extracellular domain (ECD) of the receptor initiates a series of conformational re-arrangements that culminate in the opening of the ion channel in the transmembrane domain. There are five binding sites for orthosteric ligands at the interface between the five subunits of the receptor. Experiments suggest that two or three bound glycines are sufficient to activate the receptor and that the occupancy of binding sites affects (un)binding rates. Here we evaluate the dynamics and interplay of empty and occupied binding pockets and their potential cooperativity. We investigate an ECD model for the glycine receptor, built from cryoEM data, by performing molecular dynamics simulations for different combination of ligand occupancies. We highlight the role of glycine in contracting the binding site, optimizing the water content to the amount necessary to mediate crucial interactions, and dragging Loop C to cover the pocket. Each subunit participates in two adjacent binding pockets acting in turn as principal and complementary subunit, with structures, like Loop B and Loop F, directly connected. This suggests a combination of push-pull mechanisms mediated by ligands in a potentially frustrated system, which may favour specific occupancy patterns and/or alternation of binding sites with different levels of contraction.