Anales RANF

S11-02 THE MOLECULAR DYNAMICS OF ION CONDUCTION IN P2X RECEPTORS S. Cönen 1,2 , R. Hausmann 2 , J.-P. Machtens 1,2 1 . Forschungszentrum Jülich, Jülich, Germany; 2 . RWTH Aachen University, Aachen, Germany. P2X receptors are trimeric, ligand-gated cation channels that conduct Na + , K + , and Ca 2+ ions across the cell membrane upon binding of extracellular ATP. Biochemical and electrophysiological studies have significantly advanced our understanding of P2X receptor function and regulation. In particular, high-resolution crystal structures of the human P2X3 receptor provided unprecedented insights into the architecture of the closed and open ion pore and suggested possible gating mechanisms. Furthermore, these structures visualized that opening and closing of the channel is not only determined by ATP-induced conformational changes in the extracellular domain, but also by the dynamic folding/unfolding of the so-called cytoplasmic cap, which stabilizes the open state. However, ion permeation and channel gating are inherently dynamic processes and thus challenging to study with static structures only. Here we investigate the mechanisms of ion conduction and channel gating using molecular dynamics simulations at atomic resolution. Simulations of P2X3 under physiological transmembrane voltages are used to directly observe ion permeation. Thereby we define the permeation pathways and illuminate the principles of the high cation selectivity, the ion current rectification, as well as the involvement of lipid headgroups in ion conduction. Finally, we demonstrate how the structural stability of the cytoplasmic cap determines the kinetics of receptor desensitization.