Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

19-POS Board 19 K2P Channels Characterization and Binding to Trichloroethanol Leonardo Cirqueira , Natalia Fidelis, Werner Treptow.Alessandra Kiametis. Universidade de Brasília, Brasília, Distrito Federal, Brazil.

The human two-pore domain potassium channels (K2P) is a 15 member ion channel family mostly expressed in the central nervous system. They function as leak channels, contributing with inhibitory currents to hinder neuron excitability. Studies show K2Ps play a key role in developmental syndromes, anesthesia and mental disorders, turning them into promising targets to several kinds of drugs, i.e. antipsychotics, anesthetics, antidepressants and sedatives. Recently, K2Ps crystallographic structures were published, revealing two conformations differing mainly in their M4 helix position, namely up and down. Despite these advances, there’s still the need to characterize their functional states and interaction to ligands. Tricloroethanol is a sedative used widely in pediatric and veterinary procedures. Although trichloroethanol is known to activate K2Ps its molecular mechanism remains unknown. This work aims at assessing K2Ps’ structural stability, their conduction states and at studying their interaction with trichloroethanol. Channel equilibration and structural stability, measured by the divergence to the initial crystal structure, were done with all-atom molecular dynamics (MD) simulations. To characterize if channels are conductive, ion currents were induced in simulations with electric field. The structure ensemble generated by MD was used as receptor to trichloroethanol docking searches. Equilibrium simulations indicate channels remained stable. Simulations with electric potentials are in progress. Docking calculations showed several sites in the relevant transmembrane region of the channel. Results also indicate potential conformation-dependency for ligand interaction. More accurate binding interactions will be possible with the ongoing parametrization of trichloroethanol and ensuing free energy calculations. Obtaining the equilibrium structures and making their structural, conformational and conductive characterizations are the first steps to following studies of K2P channels, like more sophisticated free energy calculation methods, gating mechanisms and other ligands’ binding sites to these K2P.

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