Papers by Lucie Delemotte
Abstract Mammalian voltage-gated sodium channels are composed of four homologous voltage sensor d... more Abstract Mammalian voltage-gated sodium channels are composed of four homologous voltage sensor domains (VSDs; DI, DII, DIII, and DIV) in which their S4 segments contain a variable number of positively charged residues. We used single histidine (H) substitutions of these charged residues in the Na v 1.4 channel to probe the positions of the S4 segments at hyperpolarized potentials. The substitutions led to the formation of gating pores that were detected as proton leak currents through the VSDs.
Biofutur, Jan 1, 2012
Résumé/Abstract Souvent absente des images simplifiées des livres de sciences de la vie, l&am... more Résumé/Abstract Souvent absente des images simplifiées des livres de sciences de la vie, l'eau est pourtant la molécule la plus abondante des systèmes biologiques. La stabilité des membranes, enveloppes de toutes les cellules du vivant, et le transport de matière au travers de celles-ci, sont largement dépendants des propriétés particulières de l'eau «interfaciale» située à leur voisinage.
Frontiers in Pharmacology, Jan 1, 2012
Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (... more Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (VGCC) has been largely understood thanks to results stemming from electrophysiology, pharmacology, spectroscopy, and structural biology. Over the past decade, computational methods such as molecular dynamics (MD) simulations have also contributed, providing molecular level information that can be tested against experimental results, thereby allowing the validation of the models and protocols. Importantly, MD can shed light on elements of VGCC function that cannot be easily accessed through “classical” experiments. Here, we review the results of recent MD simulations addressing key questions that pertain to the function and modulation of the VGCC’s voltage-sensor domain (VSD) highlighting: (1) the movement of the S4-helix basic residues during channel activation, articulating how the electrical driving force acts upon them; (2) the nature of the VSD intermediate states on transitioning between open and closed states of the VGCC; and (3) the molecular level effects on the VSD arising from mutations of specific S4 positively charged residues involved in certain genetic diseases.
Journal of Membrane Biology, Jan 1, 2012
The Journal of Physical …, Jan 1, 2008
Accurate modeling of ion transport through synthetic and biological transmembrane channels has be... more Accurate modeling of ion transport through synthetic and biological transmembrane channels has been so far a challenging problem. We introduce here a new method that allows one to study such transport under realistic biological conditions. We present results from molecular dynamics simulations of an ion channel formed by a peptide nanotube, embedded in a lipid bilayer, and subject to transmembrane potentials generated by asymmetric distributions of ions on both sides of the membrane. We show that the method is efficient for generating ionic currents and allows us to estimate the intrinsic conductance of the channel.
Biophysical journal, Jan 1, 2010
The effects on the structural and functional properties of the Kv1.2 voltage-gated ion channel, c... more The effects on the structural and functional properties of the Kv1.2 voltage-gated ion channel, caused by selective mutation of voltage sensor domain residues, have been investigated using classical molecular dynamics simulations. Following experiments that have identified mutations of voltage-gated ion channels involved in state-dependent omega currents, we observe for both the open and closed conformations of the Kv1.2 that specific mutations of S4 gating-charge residues destabilize the electrostatic network between helices of the voltage sensor domain, resulting in the formation of hydrophilic pathways linking the intra-and extracellular media. When such mutant channels are subject to transmembrane potentials, they conduct cations via these so-called ''omega pores.'' This study provides therefore further insight into the molecular mechanisms that lead to omega currents, which have been linked to certain channelopathies.
Journal of Molecular …, Jan 1, 2008
Proceedings of the …, Jan 1, 2011
The response of a membrane-bound Kv1.2 ion channel to an applied transmembrane potential has been... more The response of a membrane-bound Kv1.2 ion channel to an applied transmembrane potential has been studied using molecular dynamics simulations. Channel deactivation is shown to involve three intermediate states of the voltage sensor domain (VSD), and concomitant movement of helix S4 charges 10-15 Å along the bilayer normal; the latter being enabled by zipper-like sequential pairing of S4 basic residues with neighboring VSD acidic residues and membrane-lipid head groups. During the observed sequential transitions S4 basic residues pass through the recently discovered charge transfer center with its conserved phenylalanine residue, F 233 . Analysis indicates that the local electric field within the VSD is focused near the F 233 residue and that it remains essentially unaltered during the entire process. Overall, the present computations provide an atomistic description of VSD response to hyperpolarization, add support to the sliding helix model, and capture essential features inferred from a variety of recent experiments.
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Papers by Lucie Delemotte