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Exploring the activation mechanisms in ligand-gated ion channels by enhanced sampling methods

Mercoledý 19 aprile 2017 – 15.00, Edificio Fisica, S3 Cnr Nano, aula Seminari, Dipartimento FIM, Modena

Relatore: Carla Molteni (Dept. Physics, King's College London, UK )
Abstract: Pentameric ligand-gated ion channels (pLGICs), embedded in the membrane of nerve cells, are important neuroreceptors that mediate fast synaptic transmission, are involved in several neurological disorders and are target sites for drugs and, in invertebrates, insecticides. However, we have little idea of how these nano-machines function at the molecular level due to their complexity and limited experimental information. We have investigated the first crucial step of their activation mechanism, which consists in the binding of a neurotransmitter to their extracellular domain, focussing of the prototypical case of the neurotransmitter GABA binding to the insect RDL receptor, which is linked to the resistance to the insecticide dieldrin. Using the "funnel-metadynamics'' computational technique, which efficiently enhances the sampling of bound and unbound states using a funnel-shaped restraining potential to limit the exploration in the solvent, we have described the binding free energy landscape, identified the chain of events leading GABA from the solvent into the binding-pocket and estimated the binding affinity. Moreover, we have shown how this landscape is disrupted by mutations which prevent the receptor to function. We have also assessed the potential of a trans-cis proline switch for the opening (gating) of the ion channel in the case of the 5-HT3 receptor, which is activated by the neurotransmitter serotonin. The RDL and the 5-HT3 receptors share structural and functional features with other pLGICs, hence our work provides valuable protocols to study the activation mechanisms of these complex biomolecules beyond conventional docking and molecular dynamics techniques.

Ospiti: Stefano Corni

[Ultimo aggiornamento: 14/04/2017 10:23:57]