Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

28-POS Board 28 IN SILICO ELECTROPHYSIOLOGY OF SMALL MOLECULE REGULATION OF POTASSIUM CHANNELS Wojciech Kopec 1 ; Marcus Schewe 3 ; Aytug K Kiper 2 ; Mauricio Bedoya 4 ; Stefanie Marzian 2 ; David Ramirez 4 ; Elena B Riel 3 ; Annemarie Köhler 3 ; Rinné Susanne 2 ; Niels Decher 2 ; Bert L de Groot 1 ; Gonzalez Wendy 4,5 ; Thomas Baukrowitz 3 ; 1 Max Planck Institute for Multidisciplinary Sciences, Theoretical and Computational Biophysics, Goettingen, Germany 2 University of Marburg, Institute for Physiology and Pathophysiology, Marburg, Germany 3 Kiel University, Institute of Physiology, Kiel, Germany 4 Universidad de Talca, Centro de Bioinformática y Simulación Molecular, Talca, Chile 5 Universidad de Talca, Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Talca, Chile Potassium channels are essential proteins playing key roles in a multitude of physiological functions. These channels conduct potassium ions down their electrochemical gradient and undergo complex conformational changes between ‘open’, ‘closed’ and ‘inactivated’ states, in so-called gating transitions. Both of these features (ion conduction and gating) can be affected by interactions of a channel with small molecules, opening a way for designing new therapeutic agents targeting potassium channels. In recent years, Molecular Dynamics (MD) simulations of potassium channels matured to the level allowing for near-quantitative comparison with functional data. Therefore, simulations can now be used to study the effect of small molecules on these channels, explaining functional data and generating hypotheses on their molecular mechanism of action. Here, we will present two recent investigations of small molecules interacting with potassium channels. In the first one, we focused on the arachidonic acid (AA), a lipid molecule that targets the elusive C-type inactivation process occurring at the selectivity filter (SF) of voltage-gated potassium channels. Our simulations reveal how binding of AA from the membrane phase allosterically affects the stability of the channel SF. In the second investigation, we studied the effect of the TASK-1 channel activator ONO. In MD ONO binds to the computationally generated open state of the channel and increases its conductance. Simultaneously, the presence of ONO in the channel cavity prohibits the re-formation of the channel X-gate, leading to an enhanced open probability. Both studies are tightly related to functional investigations and show good agreement with mutational and functional observations.

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