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J Phys Chem B. 2011 Jul 14;115(27):8732-8. doi: 10.1021/jp2001964. Epub 2011 Jun 22.

Structural dynamics of the S4 voltage-sensor helix in lipid bilayers lacking phosphate groups.

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Department of Physiology and Biophysics and the Center for Biomembrane Systems, University of California, Irvine, California 92697, USA.


Voltage-dependent K(+) (Kv) channels require lipid phosphates for functioning. The S4 helix, which carries the gating charges in the voltage-sensing domain (VSD), inserts into membranes while being stabilized by a protein-lipid interface in which lipid phosphates play an essential role. To examine the physical basis of the protein-lipid interface in the absence of lipid phosphates, we performed molecular dynamics (MD) simulations of a KvAP S4 variant (S4mut) in bilayers with and without lipid phosphates. We find that, in dioleoyltrimethylammoniumpropane (DOTAP) bilayers lacking lipid phosphates, the gating charges are solvated by anionic counterions and, hence, lack the bilayer support provided by phosphate-containing palmitoyloleoylglycerophosphocholine (POPC) bilayers. The result is a water-permeable bilayer with significantly smaller deformations around the peptide. Together, these results provide an explanation for the nonfunctionality of VSDs in terms of a destabilizing protein-lipid interface.

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