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

• Published in: Scientific reports 2017-04, Vol.7 (1), p.632-632, Article 632
• Main Authors: Harrigan, Matthew P., McKiernan, Keri A., Shanmugasundaram, Veerabahu, Denny, Rajiah Aldrin, Pande, Vijay S.
• Format: Article
• Language: English
• Subjects: 119/118; 631/57/2266; 631/57/2270/1140; 631/57/2283; 631/92/612/1237; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00256-y

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.