Change search
ReferencesLink to record
Permanent link

Direct link
Dynamics of the voltage-sensor domain in voltage-gated ion channels: Studies on helical content and hydrophobic barriers within voltage-sensor domains
KTH, School of Engineering Sciences (SCI), Theoretical Physics. (Theoretical and Computational Biophysics)
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. , xi, 61 p.
Series
Trita-FYS, ISSN 0280-316X ; 2011:29
Keyword [en]
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: urn:nbn:se:kth:diva-33818ISBN: 978-91-7501-041-0OAI: oai:DiVA.org:kth-33818DiVA: diva2:417956
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
List of papers
1. 310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State
Open this publication in new window or tab >>310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State
2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 6, 1446-1454 p.Article in journal (Refereed) Published
Abstract [en]

The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 3(10)-helix in S4. This suggests S4 might make a transition from alpha- to 3(10)-helix in the gating process. Here, we show 3(10)-helix structure between 01 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as a-helix and transformed to 3(10)-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 3(10)-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 3(10) hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

National Category
Biophysics Bioinformatics and Systems Biology Theoretical Chemistry
Research subject
SRA - E-Science (SeRC)
Identifiers
urn:nbn:se:kth:diva-33480 (URN)10.1016/j.bpj.2011.02.003 (DOI)000288889700008 ()2-s2.0-79953898210 (ScopusID)
Funder
EU, European Research Council, 209825Swedish Research CouncilSwedish e‐Science Research Center
Note

QC 20150716

Available from: 2011-05-16 Created: 2011-05-09 Last updated: 2015-07-16Bibliographically approved
2. The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic core
Open this publication in new window or tab >>The voltage sensor deactivation barrier is altered by substitutions in the hydrophobic core
(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:nbn:se:kth:diva-34853 (URN)
Available from: 2011-06-16 Created: 2011-06-16 Last updated: 2016-08-16Bibliographically approved

Open Access in DiVA

fulltext(133501 kB)170 downloads
File information
File name FULLTEXT01.pdfFile size 133501 kBChecksum SHA-512
252506c26ff5a00e3d36fea58983a967ed3d0811c77e4334a75fb2f050a345f2c3d7f856fe07695be4a5e064b1acc1bd435473b896871c53c7b795ae299dc085
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Schwaiger, Christine S.
By organisation
Theoretical Physics
Condensed Matter Physics

Search outside of DiVA

GoogleGoogle Scholar
Total: 170 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 152 hits
ReferencesLink to record
Permanent link

Direct link