title: Free-energy landscape of ion-channel voltage-sensor-domain activation.
abstract: Voltage sensor domains (VSDs) are membrane-bound protein modules that confer voltage sensitivity to membrane proteins. VSDs sense changes in the transmembrane voltage and convert the electrical signal into a conformational change called activation. Activation involves a reorganization of the membrane protein charges that is detected experimentally as transient currents. These so-called gating currents have been investigated extensively within the theoretical framework of so-called discrete-state Markov models (DMMs), whereby activation is conceptualized as a series of transitions across a discrete set of states. Historically, the interpretation of DMM transition rates in terms of transition state theory has been instrumental in shaping our view of the activation process, whose free-energy profile is currently envisioned as composed of a few local minima separated by steep barriers. Here we use atomistic level modeling and well-tempered metadynamics to calculate the configurational free energy along a single transition from first principles. We show that this transition is intrinsically multidimensional and described by a rough free-energy landscape. Remarkably, a coarse-grained description of the system, based on the use of the gating charge as reaction coordinate, reveals a smooth profile with a single barrier, consistent with phenomenological models. Our results bridge the gap between microscopic and macroscopic descriptions of activation dynamics and show that choosing the gating charge as reaction coordinate masks the topological complexity of the network of microstates participating in the transition. Importantly, full characterization of the latter is a prerequisite to rationalize modulation of this process by lipids, toxins, drugs, and genetic mutations.
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122;
authors.forename: Lucie
authors.initials: L
authors.lastname: Delemotte
authors.affiliation: Université de Lorraine, Structure et Réactivité des Systèmes Moléculaires Complexes, Vandoeuvre-lés-Nancy, F-54506 France; Lomonosov Moscow State University, Moscow, 119991, Russian Federation; and.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Kasimova
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.affiliation: Université de Lorraine, Structure et Réactivité des Systèmes Moléculaires Complexes, Vandoeuvre-lés-Nancy, F-54506 France; Centre National de la Recherche Scientifique, Structure et Réactivité des Systèmes Moléculaires Complexes, Vandoeuvre-lés-Nancy, F-54506 France mounir.tarek@univ-lorraine.fr vincenzo.carnevale@temple.edu.
authors.forename: Mounir
authors.initials: M
authors.lastname: Tarek
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122; mounir.tarek@univ-lorraine.fr vincenzo.carnevale@temple.edu.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
mesh_terms: D015640:Ion Channel Gating; D051663:Kv1.2 Potassium Channel / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D051663:Kv1.2 Potassium Channel
keywords: Kv1.2; electrophysiology; gating kinetics; metadynamics; voltage-gated ion channels