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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 ?s 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.

SUBMITTER: Harrigan MP

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

REPOSITORIES: biostudies-literature

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

Harrigan Matthew P MP McKiernan Keri A KA Shanmugasundaram Veerabahu V Denny Rajiah Aldrin RA Pande Vijay S VS

Scientific reports 20170404 1

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 "pinche ...[more]

PMID: 28377596

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Dataset Information

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

Publications

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

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