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Publications (10 of 11) Show all publications
Kasimova, M. A., Tewari, D., Cowgill, J. B., Ursuleaz, W. C., Lin, J. L., Delemotte, L. & Chanda, B. (2019). Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization- dependent gating. eLIFE, 8, Article ID e53400.
Open this publication in new window or tab >>Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization- dependent gating
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e53400Article in journal (Refereed) Published
Abstract [en]

In contrast to most voltage-gated ion channels, hyperpolarization- and cAMP gated (HCN) ion channels open on hyperpolarization. Structure-function studies show that the voltagesensor of HCN channels are unique but the mechanisms that determine gating polarity remain poorly understood. All-atom molecular dynamics simulations (similar to 20 mu s) of HCN1 channel under hyperpolarization reveals an initial downward movement of the S4 voltage-sensor but following the transfer of last gating charge, the S4 breaks into two sub-helices with the lower sub-helix becoming parallel to the membrane. Functional studies on bipolar channels show that the gating polarity strongly correlates with helical turn propensity of the substituents at the breakpoint. Remarkably, in a proto-HCN background, the replacement of breakpoint serine with a bulky hydrophobic amino acid is sufficient to completely flip the gating polarity from inward to outward-rectifying. Our studies reveal an unexpected mechanism of inward rectification involving a linker sub-helix emerging from HCN S4 during hyperpolarization.

Place, publisher, year, edition, pages
NLM (Medline), 2019
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-266207 (URN)10.7554/eLife.53400 (DOI)000502276500001 ()31774399 (PubMedID)2-s2.0-85076385930 (Scopus ID)
Note

QC 20200109

Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2020-01-09Bibliographically approved
Delemotte, L. (2019). Outlining the proton-conduction pathway in otopetrin channels. Nature Structural & Molecular Biology, 26(7), 528-530
Open this publication in new window or tab >>Outlining the proton-conduction pathway in otopetrin channels
2019 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 26, no 7, p. 528-530Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-255418 (URN)10.1038/s41594-019-0260-8 (DOI)000473734400002 ()31235916 (PubMedID)2-s2.0-85068233279 (Scopus ID)
Note

QC 20190815

Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-08-15Bibliographically approved
Harpole, T. J. & Delemotte, L. (2018). Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations. Biochimica et Biophysica Acta - Biomembranes, 1860(4), 909-926
Open this publication in new window or tab >>Conformational landscapes of membrane proteins delineated by enhanced sampling molecular dynamics simulations
2018 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1860, no 4, p. 909-926Article, review/survey (Refereed) Published
Abstract [en]

The expansion of computational power, better parameterization of force fields, and the development of novel algorithms to enhance the sampling of the free energy landscapes of proteins have allowed molecular dynamics (MD) simulations to become an indispensable tool to understand the function of biomolecules. The temporal and spatial resolution of MD simulations allows for the study of a vast number of processes of interest. Here, we review the computational efforts to uncover the conformational free energy landscapes of a subset of membrane proteins: ion channels, transporters and G-protein coupled receptors. We focus on the various enhanced sampling techniques used to study these questions, how the conclusions come together to build a coherent picture, and the relationship between simulation outcomes and experimental observables.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Molecular dynamics simulations, Membrane protein, Ion channel, Transporter, G-protein coupled receptor, Free energy landscape
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-225283 (URN)10.1016/j.bbamem.2017.10.033 (DOI)000426027600012 ()29113819 (PubMedID)2-s2.0-85035114873 (Scopus ID)
Note

QC 20180403

Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2019-10-08Bibliographically approved
Andersson, A. E. V., Kasimova, M. A. & Delemotte, L. (2018). Exploring the Viral Channel Kcv(PBCV-1) Function via Computation. Journal of Membrane Biology, 251(3), 419-430
Open this publication in new window or tab >>Exploring the Viral Channel Kcv(PBCV-1) Function via Computation
2018 (English)In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 419-430Article in journal (Refereed) Published
Abstract [en]

Viral potassium channels (Kcv) are homologous to the pore module of complex -selective ion channels of cellular organisms. Due to their relative simplicity, they have attracted interest towards understanding the principles of conduction and channel gating. In this work, we construct a homology model of the open state, which we validate by studying the binding of known blockers and by monitoring ion conduction through the channel. Molecular dynamics simulations of this model reveal that the re-orientation of selectivity filter carbonyl groups coincides with the transport of potassium ions, suggesting a possible mechanism for fast gating. In addition, we show that the voltage sensitivity of this mechanism can originate from the relocation of potassium ions inside the selectivity filter. We also explore the interaction of with the surrounding bilayer and observe the binding of lipids in the area between two adjacent subunits. The model is available to the scientific community to further explore the structure/function relationship of Kcv channels.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Viral ion channel, Homology modeling, Molecular dynamics simulations, Gating, Conduction, Protein-lipid interaction
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-232416 (URN)10.1007/s00232-018-0022-2 (DOI)000437103200012 ()29476260 (PubMedID)2-s2.0-85044948443 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180725

Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2018-08-21Bibliographically approved
Groome, J. R., Moreau, A. & Delemotte, L. (2018). Gating pore currents in sodium channels. Handbook of Experimental Pharmacology, 371-399
Open this publication in new window or tab >>Gating pore currents in sodium channels
2018 (English)In: Handbook of Experimental Pharmacology, ISSN 0171-2004, E-ISSN 1865-0325, p. 371-399Article in journal (Refereed) Published
Abstract [en]

Voltage-gated sodium channels belong to the superfamily of voltage-gated cation channels. Their structure is based on domains comprising a voltage sensor domain (S1–S4 segments) and a pore domain (S5–S6 segments). Mutations in positively charged residues of the S4 segments may allow protons or cations to pass directly through the gating pore constriction of the voltage sensor domain; these anomalous currents are referred to as gating pore or omega (ω) currents. In the skeletal muscle disorder hypokalemic periodic paralysis, and in arrhythmic dilated cardiomyopathy, inherited mutations of S4 arginine residues promote omega currents that have been shown to be a contributing factor in the pathogenesis of these sodium channel disorders. Characterization of gating pore currents in these channelopathies and with artificial mutations has been possible by measuring the voltage-dependence and selectivity of these leak currents. The basis of gating pore currents and the structural basis of S4 movement through the gating pore has also been studied extensively with molecular dynamics. These simulations have provided valuable insight into the nature of S4 translocation and the physical basis for the effects of mutations that promote permeation of protons or cations through the gating pore.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Arrhythmic dilated cardiomyopathy, Gating pore, Hypokalemic periodic paralysis, Molecular dynamics, Omega current, Sodium channel, acetazolamide, diclofenamide, sodium channel Nav1.4, sodium channel Nav1.5, voltage gated sodium channel, action potential, cardiac channelopathy, channel gating, congestive cardiomyopathy, drug efficacy, gating pore current, gene mutation, human, nonhuman, phenotype, priority journal, sodium channelopathy, sodium current, animal, channelopathy, chemistry, genetics, mutation, physiology, Action Potentials, Animals, Channelopathies, Humans, Ion Channel Gating, Voltage-Gated Sodium Channels
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-236448 (URN)10.1007/164_2017_54 (DOI)2-s2.0-85048200099 (Scopus ID)
Note

QC 20181022

Available from: 2018-10-22 Created: 2018-10-22 Last updated: 2018-10-30Bibliographically approved
Westerlund, A. M., Harpole, T. J., Blau, C. & Delemotte, L. (2018). Inference of Calmodulin's Ca2+: Dependent Free Energy Landscapes via Gaussian Mixture Model Validation. Paper presented at 62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA. Biophysical Journal, 114(3), 675A-675A
Open this publication in new window or tab >>Inference of Calmodulin's Ca2+: Dependent Free Energy Landscapes via Gaussian Mixture Model Validation
2018 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 675A-675AArticle in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-227240 (URN)10.1016/j.bpj.2017.11.3640 (DOI)000430563300366 ()
Conference
62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA
Note

QC 20180518

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2019-08-20Bibliographically approved
Westerlund, A. M. & Delemotte, L. (2018). On the Selective Promiscuity of Calmodulin. Paper presented at 62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA. Biophysical Journal, 114(3), 7A-8A
Open this publication in new window or tab >>On the Selective Promiscuity of Calmodulin
2018 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, no 3, p. 7A-8AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-227241 (URN)10.1016/j.bpj.2017.11.076 (DOI)000429315800042 ()
Conference
62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA
Note

QC 20180517

Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-05-17Bibliographically approved
Delemotte, L. (2018). Opening leads to closing: Allosteric crosstalk between the activation and inactivation gates in KcsA. The Journal of General Physiology, 215(10), 1356-1359
Open this publication in new window or tab >>Opening leads to closing: Allosteric crosstalk between the activation and inactivation gates in KcsA
2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, no 10, p. 1356-1359Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Rockefeller University Press, 2018
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-236665 (URN)10.1085/jgp.201812161 (DOI)000447673900004 ()2-s2.0-85054054760 (Scopus ID)
Note

Export Date: 22 October 2018; Note; CODEN: JGPLA; Correspondence Address: Delemotte, L.; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of TechnologySweden; email: lucie.delemotte@scilifelab.se. QC 20181113

Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2018-11-13Bibliographically approved
Howard, R. J., Carnevale, V., Delemotte, L., Hellmich, U. A. & Rothberg, B. S. (2018). Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport. Biochimica et Biophysica Acta - Biomembranes, 1860(4), 927-942
Open this publication in new window or tab >>Permeating disciplines: Overcoming barriers between molecular simulations and classical structure-function approaches in biological ion transport
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2018 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1860, no 4, p. 927-942Article, review/survey (Refereed) Published
Abstract [en]

Ion translocation across biological barriers is a fundamental requirement for life. In many cases, controlling this process for example with neuroactive drugs demands an understanding of rapid and reversible structural changes in membrane-embedded proteins, including ion channels and transporters. Classical approaches to electrophysiology and structural biology have provided valuable insights into several such proteins over macroscopic, often discontinuous scales of space and time. Integrating these observations into meaningful mechanistic models now relies increasingly on computational methods, particularly molecular dynamics simulations, while surfacing important challenges in data management and conceptual alignment. Here, we seek to provide contemporary context, concrete examples, and a look to the future for bridging disciplinary gaps in biological ion transport. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin Mcllwain.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Ion transport, Ion channel, Molecular dynamics, Kinetic modeling, Structural biology, Electrophysiology
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-225284 (URN)10.1016/j.bbamem.2017.12.013 (DOI)000426027600013 ()29258839 (PubMedID)2-s2.0-85038850462 (Scopus ID)
Note

QC 20180403

Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2019-08-20Bibliographically approved
Gianti, E., Delemotte, L., Klein, M. & Carnevale, V. (2017). Exploiting water density fluctuations in ion channel drug design. Paper presented at 253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA. Abstracts of Papers of the American Chemical Society, 253
Open this publication in new window or tab >>Exploiting water density fluctuations in ion channel drug design
2017 (English)In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-242589 (URN)000430568507653 ()
Conference
253rd National Meeting of the American-Chemical-Society (ACS) on Advanced Materials, Technologies, Systems, and Processes, APR 02-06, 2017, San Francisco, CA
Note

QC 20190226

Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-08-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0828-3899

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