Helix Breaking Transition in the S4 of HCN Channel is Critical for Hyperpolarization-Dependent Gating

作     者：Kasimova, Marina A. Tewari, Debanjan Cowgill, John Ursulaez, Willy Carrasquel Lin, Jenna Delemotte, Lucie Chanda, Baron 

作者机构：Science for Life Laboratory Department of Applied Physics KTH Royal Institute of Technology Stockholm Sweden Department of Neuroscience University of Wisconsin-Madison 1111 Highland Ave. MadisonWI53705 United States Graduate program in Biophysics University of Wisconsin-Madison Department of Biomolecular Chemistry University of Wisconsin-Madison 420 Henry Mall MadisonWI53706 United States 

出 版 物：《SSRN》 

年 卷 期：2019年

核心收录：

主　　题：Free energy 

摘      要：HCN channels, unlike other members of the VGIC superfamily, open upon hyperpolarization rather than depolarization. Structural and functional analyses reveal that the voltage-sensor of these channels are unique but the mechanisms that lead to inward rectification remain poorly understood. Here, using all-atom molecular dynamics simulations under hyperpolarization conditions, we report that the S4 voltage-sensor of HCN channels initially moves downward but, upon transfer of the last gating charge, breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane plane. Substitution of the serine at the breakpoint with a hydrophobic residue favors outward rectification but this effect can be reversed by inserting a serine in an adjacent position. We find that the gating polarity strongly correlates with hydrophilicity and helical turn propensity of the substituents at the breakpoint. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization. © 2019, The Authors. All rights reserved.