The molecular dynamics of potassium channel permeation, selectivity and gating

Potassium channels are widely distributed ion channels important in many cellular processes. Despite their impressive structural heterogeneity, all potassium channels share a very well conserved selectivity filter (SF), that defines their ion permeation and selectivity properties. Our previous MD simulations of various potassium channels established novel principles of ion permeation and selectivity, and led to a proposed mechanism of selectivity filter-based gating. Our results generated novel testable hypotheses for functional studies, and similarly, were inspired by experimental predictions, highlighting the importance of a highly collaborative network provided by DynIon.

In the next funding period, we propose to investigate ion permeation mechanisms in mutated K+ channels with altered selectivity filters. Moreover, several aspects predicted by the novel gating model, postulated by us, will be tested in different K+ channels, in close collaboration with P1 and P10 (Baukrowitz/Schewe, Schröder), and its regulation will be affected with designed mutations. We will extend the studies of pharmacological regulation of potassium channels, focusing on MthK and BK channels, with P1 (Baukrowitz/Schewe) and P3 (Plested/Sun). On the development side, we aim to simulate full I/V curves of potassium channels, to connect functional data with simulations even more, as well as study large conformation changes (gating) in full-length channels, using simulations-assisted cryo-EM refinement, in collaboration with P3 (Plested/Sun) and P9 (Ziegler).