Summary: Researchers used large-scale computer simulations to reveal how protein switches in the brain open and close ion channels — a discovery that could guide the development of safer, more targeted anesthetics and other therapies.
Source: RMIT University
Advancing safer, more effective drugs and anaesthetics
Scientists at RMIT University in Melbourne have used supercomputing resources to map how ligand-gated ion channels — protein “switches” in nerve cells — are activated by binding molecules and generate electrical signals in the brain. The work, led by Professor Toby Allen with Dr. Bogdan Lev and Dr. Brett Cromer, draws on seven years of research and hundreds of millions of hours of computer processing to reveal molecular details that were previously inaccessible.
These ion channels are central to how nerve cells communicate: they convert chemical messages from neurotransmitters into the electrical currents that underpin sensation, movement and cognition. General anaesthetics act by tipping the balance of these switches — suppressing “on” signals and potentiating “off” signals — which produces loss of sensation and prevents pain. Yet, despite more than 150 years of clinical use, the precise molecular action of many anaesthetics has remained unclear.
“General anaesthetics are essential in modern medicine but have a narrow safety margin and potential long-term effects on the developing or aging brain,” Professor Allen explained. “By revealing how these ion channel switches actually bind molecules and change shape to conduct signals, our models open the door to designing anaesthetics that are both safer and more selective.”
The team used detailed all-atom molecular dynamics combined with a swarm-based string method to identify minimum free-energy pathways that describe how a representative pentameric ligand-gated ion channel transitions between closed and open states. These simulations were performed on the Victorian Life Sciences Computation Initiative and produced an unprecedented view of the gating process — how binding events at the extracellular domain translate into conformational changes that open a pore in the cell membrane.
Using transition-path analysis, the researchers identified stable wetted/open and dewetted/closed channel states, and characterized intermediate conformations that help explain how channels can close even when an agonist is present. The models reveal coordinated structural changes across three key regions: the agonist-binding extracellular domain, the ion-conducting transmembrane domain, and the gating interface that links them.
Crucially, the study describes a molecular switching mechanism that senses proton binding through a pronounced reorganization at the subunit interface. This rearrangement alters the packing of β-sheets in the extracellular domain and triggers asynchronous movements of the pore-lining M2 helices, ultimately opening or closing the ion-conducting pore. These mechanistic insights illuminate the allosteric pathways that control gating in the broader superfamily of pentameric ligand-gated ion channels.
The implications extend beyond anaesthesia. Because similar proteins are conserved across many organisms, the results may inform safer, more targeted insecticides and anti-parasitic compounds. The computational approach used in this study also reduces reliance on animal experiments during early-stage drug design by enabling predictive in silico testing of drug-channel interactions.
Funding: The work was supported by the National Health and Medical Research Council and the Medical Advances Without Animals Trust.
Source: Toby Allen — RMIT University
Original research: “String method solution of the gating pathways for a pentameric ligand-gated ion channel” by Bogdan Lev, Samuel Murail, Frédéric Poitevin, Brett A. Cromer, Marc Baaden, Marc Delarue, and Toby W. Allen. Published in PNAS, May 9, 2017. DOI: 10.1073/pnas.1617567114.
Pentameric ligand-gated ion channels mediate fast synaptic transmission by converting chemical signals into electrical responses. Agonist binding induces rapid signal transduction through an allosteric mechanism in which large-scale conformational changes open a pore across the nerve cell membrane. Using all-atom molecular dynamics coupled with a swarm-based string method, the authors solved minimum free-energy gating pathways for the proton-activated bacterial GLIC channel. The study identifies stable wetted/open and dewetted/closed states and reveals conformational rearrangements in the extracellular agonist-binding domain, the transmembrane ion-conducting domain, and the gating interface that coordinates communication between these regions. Transition analysis produces free-energy surfaces that expose possible allosteric pathways, pH-dependent stabilization, and intermediate states that facilitate channel closing despite agonist binding. The results describe a switching mechanism in which proton binding induces a marked reorganization of subunit interfaces and β-sheet packing, driving asynchronous movements of the pore-lining M2 helices. These molecular details clarify GLIC gating and provide insight into allosteric mechanisms across the pentameric ligand-gated channel superfamily.