Gating Ritual: Simulations of Gating in Glutamate-Gated Chloride Channel

Abstract

Ligand-gated ion channels (LGICs) are responsible for converting chemical signals to electrical ones in the nerve system, which is a key element in the fast synaptic signal transmission. The first crystal structures of prokaryotic homologs were solved a few years ago, and today there are many more structures available - including a human one. These structures are believed to represent both open, closed, and desensitized states, but despite this wealth of information the core question for a LGIC remains unanswered: How does the binding of the agonist couple to the transmembrane domain to cause gating?Recent crystal structures of GluCl in both apo and liganded states make GluCl an ideal model system to explore this coupling computationally. We have performed several microsecond-scale simulations of open and closed state crystal structures (3RHW, 3RIF, 4TNV ) in their native forms, and examined the effects of keeping & removing ligands as well as allosteric modulators to observe transitions events.Removal of both ligand and modulator leads to a fully closed state after more than a microsecond. Control simulations of open states (3RHW & 3RIF) display a closed hydrophobic gate (9’) at least half of the time. In 3RIF simulation, the 9’ position is more flexible and an open pore is reached within a microsecond. Although rest of the pore is open, in 3RHW such opening at 9’ almost never happens. In the open 3RIF simulations, the pore opening is correlated with an increased distance between subunits. Our simulations provide clear evidence of the coupling in dynamics between the extracellular and transmembrane domains of LGICs on microsecond scale, and show how the extracellular ligand binding affects both local structure and the pore gating more than 50A away in the transmembrane domain.