title: Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels.
abstract: Prokaryotic inwardly rectifying (KirBac) potassium channels are homologous to mammalian Kir channels. Their activity is controlled by dynamical conformational changes that regulate ion flow through a central pore. Understanding the dynamical rearrangements of Kir channels during gating requires high-resolution structure information from channels crystallized in different conformations and insight into the transition steps, which are difficult to access experimentally. In this study, we use MD simulations on wild type KirBac1.1 and an activatory mutant to investigate activation gating of KirBac channels. Full atomistic MD simulations revealed that introducing glutamate in position 143 causes significant widening at the helix bundle crossing gate, enabling water flux into the cavity. Further, global rearrangements including a twisting motion as well as local rearrangements at the subunit interface in the cytoplasmic domain were observed. These structural rearrangements are similar to recently reported KirBac3.1 crystal structures in closed and open conformation, suggesting that our simulations capture major conformational changes during KirBac1.1 opening. In addition, an important role of protein-lipid interactions during gating was observed. Slide-helix and C-linker interactions with lipids were strengthened during activation gating.
authors: †Department of Pharmacology and Toxicology, University of Vienna, 1090 Vienna, Austria.
authors: Tobias
authors: T
authors: Linder
authors: ‡Center for Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors: Shizhen
authors: S
authors: Wang
authors: †Department of Pharmacology and Toxicology, University of Vienna, 1090 Vienna, Austria.
authors: Eva-Maria
authors: EM
authors: Zangerl-Plessl
authors: ‡Center for Investigation of Membrane Excitability Diseases, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors: Colin G
authors: CG
authors: Nichols
authors: †Department of Pharmacology and Toxicology, University of Vienna, 1090 Vienna, Austria.
authors: Anna
authors: A
authors: Stary-Weinzinger
mesh_terms: D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D006860:Hydrogen Bonding; D015640:Ion Channel Gating; D050356:Lipid Metabolism; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012399:Rotation; D013816:Thermodynamics
chemical_list: D050505:Mutant Proteins; D024661:Potassium Channels, Inwardly Rectifying