Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter.

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 compre

SUBMITTER: Harrigan MP 

PROVIDER: S-EPMC5428000 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature