title: Identification of the Conformational transition pathway in PIP2 Opening Kir Channels.
abstract: The gating of Kir channels depends critically on phosphatidylinositol 4,5-bisphosphate (PIP2), but the detailed mechanism by which PIP2 regulates Kir channels remains obscure. Here, we performed a series of Targeted molecular dynamics simulations on the full-length Kir2.1 channel and, for the first time, were able to achieve the transition from the closed to the open state. Our data show that with the upward motion of the cytoplasmic domain (CTD) the structure of the C-Linker changes from a loop to a helix. The twisting of the C-linker triggers the rotation of the CTD, which induces a small downward movement of the CTD and an upward motion of the slide helix toward the membrane that pulls the inner helix gate open. At the same time, the rotation of the CTD breaks the interaction between the CD- and G-loops thus releasing the G-loop. The G-loop then bounces away from the CD-loop, which leads to the opening of the G-loop gate and the full opening of the pore. We identified a series of interaction networks, between the N-terminus, CD loop, C linker and G loop one by one, which exquisitely regulates the global conformational changes during the opening of Kir channels by PIP2.
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Li
authors.affiliation: Center of Biomechanics and Bioengineering and Key Laboratory of Microgravity (National Microgravity Laboratory), Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Shouqin
authors.initials: S
authors.lastname: Lü
authors.affiliation: School of Electrical and Electronics Engineering, Shijiazhuang Tiedao University, Shijiazhuang 050043, China.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Pang
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Suhua
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Center of Biomechanics and Bioengineering and Key Laboratory of Microgravity (National Microgravity Laboratory), Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Long
authors.affiliation: Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of Pharmacology and Toxicology for New Drug, Hebei Province, Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, US.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: An
mesh_terms: D000818:Animals; D002645:Chickens; D018360:Crystallography, X-Ray; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D056004:Molecular Dynamics Simulation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D017510:Protein Folding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary
chemical_list: C489461:Kir2.1 channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying