Using molecular dynamics to elucidate the structural basis for function in pLGICs

Ligand-gated ion channels incorporate neurotransmitter binding sites and a transmembrane ion channel into a single protein complex. At fast chemical synapses, they detect the presence of extracellular neurotransmitters and open and alter the cellular membrane potential. The pentameric ligand-gated ion channels (pLGICs), also known as the Cys-loop receptors, are a major family of neurotransmitter receptors (1). Neuroscientists and biophysicists have sought to elucidate the structural basis for the functions of these channels in ever greater detail. The recent proliferation of pLGIC crystal structures has made the goal of understanding the atomic basis for their functional properties feasible. However, the crystal structures only provide static pictures. It is their dynamic properties, the conformational changes they undergo from closed to open to desensitized states, that are of fundamental interest. Computational biophysics and molecular dynamics (MD) provide tools to bridge the gaps between the static images and to create dynamic movies, at an atomic level, of these channels as they transition between functional states. In the paper by Calimet et al. in PNAS (2), the authors sought to accomplish this goal for pLGIC members using MD based on X-ray crystal structures. The pLGIC superfamily includes receptors for acetylcholine (nACh), serotonin type 3 (5-HT3), γ-amino butyric acid (GABAA), glycine (Gly), and, in invertebrates, receptors for histamine, serotonin, and glutamate (distinct from the excitatory glutamate receptors) (1). Prokaryotic family members also exist (3). pLGICs contain five identical or homologous subunits arranged quasisymmetrically around the central channel axis. All subunits have a similar transmembrane topology, with an ∼200-aa extracellular N-terminal domain and a similarly sized C-terminal domain with four transmembrane segments (M1, M2, M3, and M4). The ligand-binding sites are located in the extracellular domain (ECD) at the subunit–subunit interface about 30 Å above the surface of the membrane (4). The channel is lined by …