title: The Molecular Mechanism of Opening the Helix Bundle Crossing (HBC) Gate of a Kir Channel.
abstract: Inwardly rectifying K(+) (Kir) channels, serving as natural molecular nanomachines, transport potassium ions across the plasma membrane of the cell. Along the ion permeation pathway, three relatively narrow regions (the selectivity filter (SF), the inner helix bundle crossing (HBC), and the cytosolic G loop) may serve as gates to control ion permeation. Our previous molecular dynamics simulations based on the crystal structure of a Kir3.1 chimera revealed the possible gating mechanism of the G loop gate. Here, we introduced a proline mutation in the inner helix and obtained a channel model of the open HBC gate. The open HBC gate reaches 0.6 nm in diameter, which allows partial hydrated K(+) ions to pass through. During the gating process, both the transmembrane helices TM1 and TM2 cooperatively rotate in a counterclockwise direction (viewed from the extracellular side) with the aid of the phospholipid PIP2. Only when all the transmembrane helices adopt a counterclockwise rotation, the HBC gate can be stabilized in the open state. We estimate that introduction of the proline mutation decreases the energy required to open the HBC gate by about 1.4 kcal/mol (ΔΔG).
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.|Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Xuan-Yu
authors.initials: XY
authors.lastname: Meng
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Shengtang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.|IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.|Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions; D042201:Magnetospirillum / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009038:Motion; D009154:Mutation; D010743:Phospholipids / Q000737:chemistry; D011188:Potassium / Q000737:chemistry; D025341:Principal Component Analysis; D011485:Protein Binding; D000072417:Protein Domains; D012399:Rotation; D013816:Thermodynamics
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007477:Ions; D010743:Phospholipids; D011188:Potassium