Abstract
Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.
Highlights
TREK-2 is a member of the human K2P family of tandem-pore potassium channels
We applied molecular dynamics and Markov state models (MSMs) analysis to predict that a novel pinched state favored during membrane compression represents a low-conducting state of the TREK-2 K2P potassium channel
After simulating the TREK-2 channel for 195 μs, we discover a novel selectivity filter conformation highly preferred by the Down state, but disfavored by the down-like I1 and I2 metastable intermediates and Up state
Summary
TREK-2 is a member of the human K2P family of tandem-pore potassium channels. This protein is responsible for leak currents in most cells. Recent evidence suggests that the regulatory processes acting on this channel modulate conductance through structurally distinct mechanisms[4]. Potassium channel ion conductance is mediated by both an intracellular and interior gating process. The former involves large-scale rearrangements of the intracellular domains of the channel’s transmembrane helices to sterically block passage of ions. Interior gating involves smaller conformational changes occurring directly in the channel’s selectivity filter (SF), so named for its role in conferring potassium selectivity to the channel. Time-structure based independent component analysis (tICA) is a component of Markov state modeling that can aid in interpretability. Potential of mean force (PMF) computations can complement MSM analysis by offering quantification of free-energy profiles along paths or coordinates of interest[15]
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