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Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Tampere universitet.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: PLoS computational biology, ISSN 1553-7358, Vol. 5, no 2, e1000289- p.Article in journal (Refereed) Published
Abstract [en]

Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

Place, publisher, year, edition, pages
Public Library of Science , 2009. Vol. 5, no 2, e1000289- p.
National Category
Chemical Sciences
Research subject
Biophysics; Biochemistry
URN: urn:nbn:se:su:diva-36647DOI: 10.1371/journal.pcbi.1000289ISI: 000263924500005PubMedID: 19229308OAI: diva2:289870
Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2011-11-02Bibliographically 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.
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
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)
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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