title: 3₁₀-helix conformation facilitates the transition of a voltage sensor S4 segment toward the down state.
abstract: The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 3(10)-helix in S4. This suggests S4 might make a transition from α- to 3(10)-helix in the gating process. Here, we show 3(10)-helix structure between Q1 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as α-helix and transformed to 3(10)-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 3(10)-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 3(10) hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.
authors.affiliation: Theoretical and Computational Biophysics, Department of Theoretical Physics and Swedish e-Science Research Center, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Schwaiger
authors.forename: Pär
authors.initials: P
authors.lastname: Bjelkmar
authors.forename: Berk
authors.initials: B
authors.lastname: Hess
authors.forename: Erik
authors.initials: E
authors.lastname: Lindahl
mesh_terms: D001120:Arginine; D004560:Electricity; D018698:Glutamic Acid; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009068:Movement; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012399:Rotation
chemical_list: D007473:Ion Channels; D018698:Glutamic Acid; D001120:Arginine