title: The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel.
abstract: 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.
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Molecular Simulations and Design Group, Magdeburg, Germany.
authors.forename: Samira
authors.initials: S
authors.lastname: Yazdi
authors.affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Molecular Simulations and Design Group, Magdeburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
authors.affiliation: Science for Life Laboratory, Stockholm and Uppsala, Stockholm, Sweden.|Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Andersson
authors.affiliation: Science for Life Laboratory, Stockholm and Uppsala, Stockholm, Sweden.|Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm, Sweden.|Department of Biochemistry and Biophysics, Center for Biomembrane Research, Stockholm University, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lindahl
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D051637:Shaker Superfamily of Potassium Channels