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The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic core
KTH, School of Engineering Sciences (SCI), Theoretical Physics. (Theoretical and Computational Biophysics)
Linköping University, Department of Clinical and Experimental Medicine, Divison of Cell Biology, Linköping, Sweden.
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0002-7498-7763
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The gating of voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor moving in response to an external potential. Exactly how this is accomplished is not yet fully known, but several studies now indicate S4 transiently adopts 310-conformation to facilitate the process. Here, we combine modeling of intermediate states based on experimental constraints with systematic in silico mutagenesis and free energy calculations to identify metastable states and characterize the energetics when moving between them. We show that states very close to the X-ray structure can be obtained with steered simulations starting from the intermediate state, and that several residues in the narrow hydrophobic band in the middle of the voltage sensor contribute to the free energy between the activated and intermediate states. The single most important is the structural barrier caused by the aromatic ring of F233. Substitution for smaller amino acids reduces the translation cost signi cantly, while introduction of a larger ring increases it, both con rming experimental activation shift results. In fact, the rigid ring appears to determine the barrier for the voltage sensor gating process, with a close interaction between the ring rotation and the arginine barrier crossing.

 

National Category
Condensed Matter Physics
Identifiers
URN: urn:nbn:se:kth:diva-34853OAI: oai:DiVA.org:kth-34853DiVA, id: diva2:423873
Available from: 2011-06-16 Created: 2011-06-16 Last updated: 2016-08-16Bibliographically approved
In thesis
1. Dynamics of the voltage-sensor domain in voltage-gated ion channels: Studies on helical content and hydrophobic barriers within voltage-sensor domains
Open this publication in new window or tab >>Dynamics of the voltage-sensor domain in voltage-gated ion channels: Studies on helical content and hydrophobic barriers within voltage-sensor domains
2011 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in neural excitability and thus dysfunctional channels can cause disease. Understanding how the voltage-sensor of these channels activate and inactivate could potentially be useful in future drug design of compounds targeting neuronal excitability.

The opening and closing of the pore in voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor domain (VSD) moving in response to an external potential. Exactly how this movement is accomplished is not yet fully known and an area of hot debate. In this thesis I study how the opening and closing in voltage-gated potassium (Kv) channels occurs.

Recently, both experimental and computational results have pointed to the possibility of a secondary structure transition from α- to 3(10)-helix in S4 being an important part of the gating. First, I show that the 3(10)-helix structure in the S4 helix of a Kv1.2-2.1 chimera protein is significantly more favorable compared to the α-helix in terms of a lower free energy barrier during the gating motion. Additional I suggest a new gating model for S4, moving as sliding 310-helix. Interestingly, the single most conserved residue in voltage- gated ion channels is a phenylalanine located in the hydrophobic core and directly facing S4 causing a barrier for the gating charges.

In a second study, I address the problem of the energy barrier and show that mutations of the phenylalanine directly alter the free energy barrier of the open to closed transition for S4. Mutations can either facilitate the relaxation of the voltage-sensor or increase the free energy barrier, depending on the size of the mutant. These results are confirmed by new experimental data that supports that a rigid, cyclic ring at the phenylalanine position is the determining rate-limiting factor for the voltage sensor gating process.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. p. xi, 61
Series
Trita-FYS, ISSN 0280-316X ; 2011:29
Keywords
activation, deactivation, inactivation, voltage-sensor, VSD, Kv1.2- 2.1, F233, hydrophobic barrier, alpha-helix, 3(10)-helix
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-33818 (URN)978-91-7501-041-0 (ISBN)
Presentation
2011-06-15, Sal FA31, Roslagstullsbacken 21, AlbaNova, Stockholm, 15:00
Opponent
Supervisors
Note
QC 20110616Available from: 2011-06-16 Created: 2011-05-19 Last updated: 2011-06-16Bibliographically approved

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