Ion channels are membrane proteins that allow transport of ions across otherwise impermeable membrane. Their dysfunction often results in severe hereditary diseases, underlying the importance of ion channels as pharmacological targets. Characterization of ion channel structure and function (gating) is a necessary step towards the design of their modulators. We are particularly interested in voltage-gated ion channels, which open or close an ion-selective pore via conformational changes that are triggered by changes in membrane voltage. We use molecular dynamics simulations, enhanced sampling methods and machine learning approaches corroborated by experiments from our collaborators (Baron Chanda, Washington University in Saint Louis, Jianmin Cui, Washington University in Saint Louis, Peter Ruben, Simon Fraser University, Fredrik Elinder, Linköping University – Ann McDermott, Columbia University).
Voltage-gated sodium and potassium channels
Voltage-gated sodium and potassium channels are the main players in shaping the electrical signals called action potentials in neuronal and muscle cells. We study the voltage-dependent mechanism by which these channels transition between different states (resting, open and inactive) and we investigate the allosteric coupling between voltage-sensor domains (VSDs) and the central channel pore. We also study the channels’ modulation by perturbations from drugs and small molecules, lipids, mutations and post-translational modification.
KcsA potassium channel
KcsA is a pH-gated bacterial potassium channel. It was the first X-ray structure ever obtained of an ion channel. Due to its simplicity and high homology with potassium channels of higher organisms it is the ideal model system, the hydrogen atom of ion channels. Despite this apparent simplicity many aspects of its behavior are still highly debated. We study KcsA’s gating mechanisms, conductance and lipid-protein interactions.
Non domain-swapped ion channels
Non domain swapped voltage-gated ion channels gather different families of tetrameric channels which share a common specific architecture in which the voltage sensor and the pore domains of the same monomer are in contact with each other. Despite their similar 3D organisation, they display different mechanisms of gating. We are thus interested in understanding the coupling between the voltage sensor and pore domains within two main families – KCNH and HCN channels – to highlight common and different features by using and analyzing extensive/long MD simulations.
Perturbation by external electric fields
Voltage-gated ion channels normally operate under membrane voltages, which are on the order of 10-100 mV. However, when we expose cells to external electric fields, the membrane voltage can increase far beyond the physiological range and exceed several 100 mV. We can computationally predict voltage-sensing elements in any membrane protein, independent of its structure or function, by applying external electric fields in simulations. We are also interested in how high-intensity electric fields used in electroporation perturb the structure and function of different voltage-gated ion channels. This information is important for clinical applications where electroporation is used to transiently increase cell membrane permeability in order to enhance the intracellular delivery of therapeutic molecules.
Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity MR Ghovanloo, K Choudhury, TS Bandaru, MA Fouda, K Rayani, R Rusinova, T Phaterpekar, K Nelkenbrecher, AR Watkins, D Poburko, J Thewalt, OS Andersen, L Delemotte, SJ Goodchild , PC Ruben.
J. . DOI: 10.1085/jgp.202012701
Informing NMR experiments with molecular dynamics simulations to characterize the dominant activated state of the KcsA ion channel S Pérez-Conesa, EG Keeler, D Zhang, L Delemotte, AE McDermott.
J. Chem. Phys., 2021. DOI: 10.1063/5.0040649
Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening W Kang, AM Westerlund, J Shi,K McFarland White, AK Dou, AH Cui, JR Silva, Lucie Delemotte, J Cui.
Sci Adv., 2020 DOI: 10.1126/sciadv.abd6798
Pulsed electric fields can create pores in the voltage sensors of voltage-gated ion channels L Rems, MA Kasimova, I Testa, L Delemotte.
Biophys J., 2020 DOI: 10.1016/j.bpj.2020.05.030
Helix breaking transition in the S4 of HCN channel is critical for hyperpolarization-dependent gating MA Kasimova, D Tewari, JB Cowgill, W Carrasquel Ursuleaz, JL Lin, L Delemotte, B Chanda.
eLife, 2019. DOI: 10.7554/eLife.53400
Outlining the proton-conduction pathway in otopetrin channels L Delemotte.
Nat. Struct. Mol. Biol., 2019. DOI:10.1038/s41594-019-0260-8
Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel AI Fernández-Mariño, TJ Harpole, K Oelstrom, L Delemotte and B Chanda.
Nat. Struct. Mol. Biol., 2018. DOI: 10.1038/s41594-018-0047-3
Exploring the Viral Channel KcvPBCV‑1 Function via Computation 1007/s00232-018-0022-2
Studying Kv Channels Function using Computational Methods A Deyawe, MA Kasimova, L Delemotte, G Loussouarn, M Tarek.
Potassium Channels, 2017. DOI: 10.1007/978-1-4939-7362-0_24
Does proton conduction in the voltage-gated H+ channel hHv1 involve grotthuss-like hopping via acidic residues? S C van Keulen, E Gianti, V Carnevale, ML Klein, U Rothlisberger and L Delemotte.
J. Phys. Chem. B, 2017 DOI: 10.1021/acs.jpcb.6b08339
Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin K Elokely, P Velisetty, L Delemotte, E Palovcak, ML Klein, T Rohacs, V Carnevale.
PNAS, 2016. DOI: 10.1073/pnas.1517288113
Gating pore currents are defects in common with two Nav1. 5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy A Moreau, P Gosselin-Badaroudine, L Delemotte, ML Klein, M Chahine
The Journal of general physiology, 2015. DOI: 10.1085/jgp.201411304
Free-energy landscape of ion-channel voltage-sensor–domain activation L Delemotte, MA Kasimova, ML Klein, M Tarek, V Carnevale.
PNAS, 2015. DOI: 10.1073/pnas.1416959112
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