The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel

PLoS Comput Biol. 2016 Jan 11;12(1):e1004704. doi: 10.1371/journal.pcbi.1004704. eCollection 2016 Jan.


Voltage-gated potassium (KV) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker KV channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker KV channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computational Biology
  • Fatty Acids, Unsaturated / chemistry*
  • Fatty Acids, Unsaturated / metabolism*
  • Models, Molecular
  • Shaker Superfamily of Potassium Channels / chemistry*
  • Shaker Superfamily of Potassium Channels / metabolism*


  • Fatty Acids, Unsaturated
  • Shaker Superfamily of Potassium Channels

Grants and funding

This work was supported by grants from The Max Planck Society for the Advancement of Science and the Excellence Initiative “Research Center for Dynamic Systems: Biosystems Engineering” to MS, The Swedish Research Council, The Swedish Heart-Lung Foundation, and The Swedish Brain Foundation to FE, Marie Curie Career Integration Grant (FP7-MC-CIG-618558), Magnus Bergvalls Stiftelse (2014-00170), and Åke Wibergs Stiftelse (M14-0245) to MA, the Swedish e-Science Research Center (SeRC) and the Swedish Research Council (2013-5901) to EL. Computational resources were provided by the Swedish National Infrastructure for Computing (2014/11-33). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.