title: 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 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.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Matthew P
authors.identifier: http://orcid.org/0000-0001-9412-0553
authors.initials: MP
authors.lastname: Harrigan
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Keri A
authors.identifier: http://orcid.org/0000-0002-4414-2567
authors.initials: KA
authors.lastname: McKiernan
authors.affiliation: Medicinal Sciences, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA.
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.affiliation: Medicinal Sciences, Pfizer Inc., 610 Main Street, Cambridge, MA, 02139, USA. Aldrin.Denny@pfizer.com.
authors.forename: Rajiah Aldrin
authors.initials: RA
authors.lastname: Denny
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA, 94305, USA. pande@stanford.edu.|Department of Computer Science, Stanford University, Stanford, CA, 94305, USA. pande@stanford.edu.|Department of Structural Biology, Stanford University, Stanford, CA, 94305, USA. pande@stanford.edu.|Program in Biophysics, Stanford University, Stanford, CA, 94305, USA. pande@stanford.edu.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008390:Markov Chains; D008958:Models, Molecular; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D007477:Ions; C503438:KCNK10 protein, human; D024683:Potassium Channels, Tandem Pore Domain