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Modeling of voltage-gated ion channels
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. (Erik Lindahl)
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 [en]
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: urn:nbn:se:su:diva-63437ISBN: 978-91-7447-336-0 (print)OAI: oai:DiVA.org:su-63437DiVA: diva2:453207
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
List of papers
1. Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.
Open this publication in new window or tab >>Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel.
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
National Category
Chemical Sciences
Research subject
Biophysics; Biochemistry
Identifiers
urn:nbn:se:su:diva-36647 (URN)10.1371/journal.pcbi.1000289 (DOI)000263924500005 ()19229308 (PubMedID)
Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2011-11-02Bibliographically approved
2. 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 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
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-63438 (URN)10.1016/j.bpj.2011.02.003 (DOI)
Available from: 2011-11-01 Created: 2011-10-18 Last updated: 2017-12-08Bibliographically approved
3. Tracking a complete voltage-sensor cycle with metal-ion bridges
Open this publication in new window or tab >>Tracking a complete voltage-sensor cycle with metal-ion bridges
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(English)Manuscript (preprint) (Other academic)
National Category
Chemical Sciences Biological Sciences
Identifiers
urn:nbn:se:su:diva-63440 (URN)
Available from: 2011-11-01 Created: 2011-10-18 Last updated: 2011-11-02Bibliographically approved
4. Membrane Proteins Diffuse as Dynamic Complexes with Lipids
Open this publication in new window or tab >>Membrane Proteins Diffuse as Dynamic Complexes with Lipids
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2010 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 132, no 22, 7574-+ p.Article in journal (Refereed) Published
Abstract [en]

We describe how membrane proteins diffuse laterally in the membrane plane together with the lipids surrounding them. We find a number of intriguing phenomena. The lateral displacements of the protein and the lipids are strongly correlated, as the protein and the neighboring lipids form a dynamical protein-lipid complex, consisting of similar to 50-100 lipids. The diffusion of the lipids in the complex is much slower compared to the rest of the lipids. We also find a strong directional correlation between the movements of the protein and the lipids in its vicinity. The results imply that in crowded membrane environments there are no ""free"" lipids, as they are all influenced by the protein structure and dynamics. Our results indicate that, in studies of cell membranes, protein and lipid dynamics have to be considered together.

Place, publisher, year, edition, pages
American Chemical Society, 2010
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-50526 (URN)10.1021/ja101481b (DOI)000278837100005 ()
Note
authorCount :8Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2017-12-11Bibliographically approved
5. Molecular Dynamics Simulation of the Antiamoebin Ion Channel: Linking Structure and Conductance
Open this publication in new window or tab >>Molecular Dynamics Simulation of the Antiamoebin Ion Channel: Linking Structure and Conductance
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2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 10, 2394-402 p.Article in journal (Refereed) Published
Abstract [en]

Molecular-dynamics simulations were carried out to ascertain which of the potential multimeric forms of the transmembrane peptaibol channel, antiamoebin, is consistent with its measured conductance. Estimates of the conductance obtained through counting ions that cross the channel and by solving the Nernst-Planck equation yield consistent results, indicating that the motion of ions inside the channel can be satisfactorily described as diffusive. The calculated conductance of octameric channels is markedly higher than the conductance measured in single channel recordings, whereas the tetramer appears to be nonconducting. The conductance of the hexamer was estimated to be 115 ± 34 pS and 74 ± 20 pS, at 150 mV and 75 mV, respectively, in satisfactory agreement with the value of 90 pS measured at 75 mV. On this basis, we propose that the antiamoebin channel consists of six monomers. Its pore is large enough to accommodate K+ and Cl with their first solvation shells intact. The free energy barrier encountered by K+ is only 2.2 kcal/mol whereas Cl encounters a substantially higher barrier of nearly 5 kcal/mol. This difference makes the channel selective for cations. Ion crossing events are shown to be uncorrelated and follow Poisson statistics.

Place, publisher, year, edition, pages
Cell Press, 2011
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-63439 (URN)10.1016/j.bpj.2011.03.054 (DOI)
Available from: 2011-11-01 Created: 2011-10-18 Last updated: 2017-12-08Bibliographically approved
6. Implementation of the CHARMM Force Field in GROMACS: Analysis of Protein Stability Effects from Correction Maps, Virtual Interaction Sites, and Water Models
Open this publication in new window or tab >>Implementation of the CHARMM Force Field in GROMACS: Analysis of Protein Stability Effects from Correction Maps, Virtual Interaction Sites, and Water Models
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2010 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 2, 459-466 p.Article in journal (Refereed) Published
Abstract [en]

CHARMM27 is a widespread and popular force field for biomolecular simulation, and several recent algorithms such as implicit solvent models have been developed specifically for it. We have here implemented the CHARMM force field and all necessary extended functional forms in the GROMACS molecular simulation package, to make CHARMM-specific features available and to test them in combination with techniques for extended time steps, to make all major force fields available for comparison studies in GROMACS, and to test various solvent model optimizations, in particular the effect of Lennard-Jones interactions on hydrogens. The implementation has full support both for CHARMM-specific features such as multiple potentials over the same dihedral angle and the grid-based energy correction map on the , ψ protein backbone dihedrals, as well as all GROMACS features such as virtual hydrogen interaction sites that enable 5 fs time steps. The medium-to-long time effects of both the correction maps and virtual sites have been tested by performing a series of 100 ns simulations using different models for water representation, including comparisons between CHARMM and traditional TIP3P. Including the correction maps improves sampling of near native-state conformations in our systems, and to some extent it is even able to refine distorted protein conformations. Finally, we show that this accuracy is largely maintained with a new implicit solvent implementation that works with virtual interaction sites, which enables performance in excess of 250 ns/day for a 900-atom protein on a quad-core desktop computer.

Place, publisher, year, edition, pages
Washington: American Chemical Society, 2010
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-38245 (URN)10.1021/ct900549r (DOI)000274838800012 ()
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2017-12-12Bibliographically approved

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