title: Gating Charge Calculations by Computational Electrophysiology Simulations.
abstract: Electrical cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the molecular details of voltage sensing remain insufficiently understood. Here, we present a molecular dynamics simulation-based method to determine the underlying charge movement across the membrane-the gating charge-by measuring electrical capacitor properties of membrane-embedded proteins. We illustrate the approach by calculating the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1.2 K+channel and the voltage sensor of the Ciona intestinalis voltage-sensitive phosphatase, against experimental data. We then use the gating charge analysis to study how the T1 domain modifies voltage sensing in Kv1.2 channels and to investigate the voltage dependence of the initial binding of two Na+ions in Na+-coupled glutamate transporters. Our simulation approach quantifies various mechanisms of voltage sensing, enables direct comparison with experiments, and supports mechanistic interpretation of voltage sensitivity by fractional amino acid contributions.
authors.affiliation: Institute of Complex Systems, Zelluläre Biophysik (ICS-4) and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany. Electronic address: j.machtens@fz-juelich.de.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Machtens
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Briones
authors.affiliation: Institute of Complex Systems, Zelluläre Biophysik (ICS-4) and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alleva
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
authors.affiliation: Institute of Complex Systems, Zelluläre Biophysik (ICS-4) and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fahlke
mesh_terms: D000465:Algorithms; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D002938:Ciona intestinalis / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004594:Electrophysiology; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015640:Ion Channel Gating; D051663:Kv1.2 Potassium Channel / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D012964:Sodium / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; D015700:HIV Envelope Protein gp41; D051663:Kv1.2 Potassium Channel; D012964:Sodium