Homology modeling and molecular dynamics simulations of the alpha1 glycine receptor reveals different states of the channel.

Homology modeling is used to build initial models of the transmembrane domain of the human alpha1 glycine receptor (GlyR) based on the most recently published refined structure of nAChR (PDB ID: 2BG9). Six preliminary GlyR models are constructed using two different approaches. In one approach, five different homopentamers are built by symmetric assembly of alpha1 GlyR subunits using only one of the five unique chains of nAChR as a template. In a second approach, each nAChR subunit serves as a template for an alpha1 GlyR subunit. All six initial GlyR constructs are then embedded into a hydrated POPC lipid bilayer and subjected to molecular dynamics simulation for at least six nanoseconds. Each model is stable throughout the simulation, and the final models fall into three distinct categories. Homopentameric GlyR bundles using a single alpha nAChR subunit as a template appear to be in an open conformation. Under an applied external potential, permeation of Cl(-) ions is observed within several ns in a channel built on an alpha chain. Model channels built on non-alpha chains have a constriction either near the intracellular mouth or more centrally located in the pore domain, both of which may be narrow enough to close the channel and whose locations correspond to putative gates observed in nicotinicoid receptors. The differences between these three general models suggest that channel closure may be effected by either rotation or tangential tilting of TM2.