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310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State
Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology. (Erik Lindahl)
Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology. (Erik Lindahl)
Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
Theoretical and Computational Biophysics, Department of Theoretical Physics, Royal Institute of Technology.
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 310-helix in S4. This suggests S4 might make a transition from α- to 310-helix in the gating process. Here, we show 310-helix structure between Q1 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 α-helix and transformed to 310-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 310-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 310 hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

Place, publisher, year, edition, pages
Cell Press , 2011. Vol. 100, no 6, 1446-1454 p.
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-63438DOI: 10.1016/j.bpj.2011.02.003OAI: oai:DiVA.org:su-63438DiVA: diva2:453183
Available from: 2011-11-01 Created: 2011-10-18 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Modeling of voltage-gated ion channels
Open this publication in new window or tab >>Modeling of voltage-gated ion channels
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The recent determination of several crystal structures of voltage-gated ion channels has catalyzed computational efforts of studying these remarkable molecular machines that are able to conduct ions across biological membranes at extremely high rates without compromising the ion selectivity.

Starting from the open crystal structures, we have studied the gating mechanism of these channels by molecular modeling techniques. Firstly, by applying a membrane potential, initial stages of the closing of the channel were captured, manifested in a secondary-structure change in the voltage-sensor. In a follow-up study, we found that the energetic cost of translocating this 310-helix conformation was significantly lower than in the original conformation. Thirdly, collaborators of ours identified new molecular constraints for different states along the gating pathway. We used those to build new protein models that were evaluated by simulations. All these results point to a gating mechanism where the S4 helix undergoes a secondary structure transformation during gating.

These simulations also provide information about how the protein interacts with the surrounding membrane. In particular, we found that lipid molecules close to the protein diffuse together with it, forming a large dynamic lipid-protein cluster. This has important consequences for the understanding of protein-membrane interactions and for the theories of lateral diffusion of membrane proteins.

Further, simulations of the simple ion channel antiamoebin were performed where different molecular models of the channel were evaluated by calculating ion conduction rates, which were compared to experimentally measured values. One of the models had a conductance consistent with the experimental data and was proposed to represent the biological active state of the channel.

Finally, the underlying methods for simulating molecular systems were probed by implementing the CHARMM force field into the GROMACS simulation package. The implementation was verified and specific GROMACS-features were combined with CHARMM and evaluated on long timescales. The CHARMM interaction potential was found to sample relevant protein conformations indifferently of the model of solvent used.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics. Stockholm University, 2011. 65 p.
Keyword
Molecular modeling, Molecular dynamics, Voltage-gating, Ion channels, Protein structure prediction
National Category
Theoretical Chemistry Bioinformatics (Computational Biology)
Research subject
Biochemistry with Emphasis on Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-63437 (URN)978-91-7447-336-0 (ISBN)
Public defence
2011-12-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.Available from: 2011-11-24 Created: 2011-10-18 Last updated: 2011-11-23Bibliographically approved

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