| Related Articles |
Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter.
Sci Rep. 2017 Apr 04;7(1):632
Authors: Harrigan MP, McKiernan KA, Shanmugasundaram V, Denny RA, Pande VS
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.
PMID: 28377596 [PubMed – in process]