Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion

D. Boda, Mónika Valiskó, Douglas Henderson, Bob Eisenberg, Dirk Gillespie, Wolfgang Nonner

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

A physical model of selective "ion binding" in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion-ion and ion-dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter. Experimental conditions involving binary mixtures of alkali and/or alkaline earth metal ions are computed using equilibrium Monte Carlo simulations in the grand canonical ensemble. The model pore rejects alkali metal ions in the presence of biological concentrations of Ca2+ and predicts the blockade of alkali metal ion currents by micromolar Ca2+. Conductance patterns observed in varied mixtures containing Na+ and Li+, or Ba2+ and Ca2+, are predicted. Ca2+ is substantially more potent in blocking Na+ current than Ba2+. In apparent contrast to experiments using buffered Ca2+ solutions, the predicted potency of Ca2+ in blocking alkali metal ion currents depends on the species and concentration of the alkali metal ion, as is expected if these ions compete with Ca2+ for the pore. These experiments depend on the problematic estimation of Ca2+ activity in solutions buffered for Ca2+ and pH in a varying background of bulk salt. Simulations of Ca2+ distribution with the model pore bathed in solutions containing a varied amount of Li+ reveal a "barrier and well" pattern. The entry/exit barrier for Ca2+ is strongly modulated by the Li+ concentration of the bath, suggesting a physical explanation for observed kinetic phenomena. Our simulations show that the selectivity of L-type calcium channels can arise from an interplay of electrostatic and hard-core repulsion forces among ions and a few crucial channel atoms. The reduced system selects for the cation that delivers the largest charge in the smallest ion volume.

Original languageEnglish
Pages (from-to)497-509
Number of pages13
JournalJournal of General Physiology
Volume133
Issue number5
DOIs
Publication statusPublished - May 2009

Fingerprint

L-Type Calcium Channels
Static Electricity
Ions
Alkali Metals
Cations
Alkaline Earth Metals
Alkalies
Baths

ASJC Scopus subject areas

  • Physiology

Cite this

Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion. / Boda, D.; Valiskó, Mónika; Henderson, Douglas; Eisenberg, Bob; Gillespie, Dirk; Nonner, Wolfgang.

In: Journal of General Physiology, Vol. 133, No. 5, 05.2009, p. 497-509.

Research output: Contribution to journalArticle

Boda, D, Valiskó, M, Henderson, D, Eisenberg, B, Gillespie, D & Nonner, W 2009, 'Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion', Journal of General Physiology, vol. 133, no. 5, pp. 497-509. https://doi.org/10.1085/jgp.200910211
Boda, D. ; Valiskó, Mónika ; Henderson, Douglas ; Eisenberg, Bob ; Gillespie, Dirk ; Nonner, Wolfgang. / Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion. In: Journal of General Physiology. 2009 ; Vol. 133, No. 5. pp. 497-509.
@article{d9dd79b91a74484dae862fc886b5fea5,
title = "Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion",
abstract = "A physical model of selective {"}ion binding{"} in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion-ion and ion-dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter. Experimental conditions involving binary mixtures of alkali and/or alkaline earth metal ions are computed using equilibrium Monte Carlo simulations in the grand canonical ensemble. The model pore rejects alkali metal ions in the presence of biological concentrations of Ca2+ and predicts the blockade of alkali metal ion currents by micromolar Ca2+. Conductance patterns observed in varied mixtures containing Na+ and Li+, or Ba2+ and Ca2+, are predicted. Ca2+ is substantially more potent in blocking Na+ current than Ba2+. In apparent contrast to experiments using buffered Ca2+ solutions, the predicted potency of Ca2+ in blocking alkali metal ion currents depends on the species and concentration of the alkali metal ion, as is expected if these ions compete with Ca2+ for the pore. These experiments depend on the problematic estimation of Ca2+ activity in solutions buffered for Ca2+ and pH in a varying background of bulk salt. Simulations of Ca2+ distribution with the model pore bathed in solutions containing a varied amount of Li+ reveal a {"}barrier and well{"} pattern. The entry/exit barrier for Ca2+ is strongly modulated by the Li+ concentration of the bath, suggesting a physical explanation for observed kinetic phenomena. Our simulations show that the selectivity of L-type calcium channels can arise from an interplay of electrostatic and hard-core repulsion forces among ions and a few crucial channel atoms. The reduced system selects for the cation that delivers the largest charge in the smallest ion volume.",
author = "D. Boda and M{\'o}nika Valisk{\'o} and Douglas Henderson and Bob Eisenberg and Dirk Gillespie and Wolfgang Nonner",
year = "2009",
month = "5",
doi = "10.1085/jgp.200910211",
language = "English",
volume = "133",
pages = "497--509",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion

AU - Boda, D.

AU - Valiskó, Mónika

AU - Henderson, Douglas

AU - Eisenberg, Bob

AU - Gillespie, Dirk

AU - Nonner, Wolfgang

PY - 2009/5

Y1 - 2009/5

N2 - A physical model of selective "ion binding" in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion-ion and ion-dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter. Experimental conditions involving binary mixtures of alkali and/or alkaline earth metal ions are computed using equilibrium Monte Carlo simulations in the grand canonical ensemble. The model pore rejects alkali metal ions in the presence of biological concentrations of Ca2+ and predicts the blockade of alkali metal ion currents by micromolar Ca2+. Conductance patterns observed in varied mixtures containing Na+ and Li+, or Ba2+ and Ca2+, are predicted. Ca2+ is substantially more potent in blocking Na+ current than Ba2+. In apparent contrast to experiments using buffered Ca2+ solutions, the predicted potency of Ca2+ in blocking alkali metal ion currents depends on the species and concentration of the alkali metal ion, as is expected if these ions compete with Ca2+ for the pore. These experiments depend on the problematic estimation of Ca2+ activity in solutions buffered for Ca2+ and pH in a varying background of bulk salt. Simulations of Ca2+ distribution with the model pore bathed in solutions containing a varied amount of Li+ reveal a "barrier and well" pattern. The entry/exit barrier for Ca2+ is strongly modulated by the Li+ concentration of the bath, suggesting a physical explanation for observed kinetic phenomena. Our simulations show that the selectivity of L-type calcium channels can arise from an interplay of electrostatic and hard-core repulsion forces among ions and a few crucial channel atoms. The reduced system selects for the cation that delivers the largest charge in the smallest ion volume.

AB - A physical model of selective "ion binding" in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion-ion and ion-dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter. Experimental conditions involving binary mixtures of alkali and/or alkaline earth metal ions are computed using equilibrium Monte Carlo simulations in the grand canonical ensemble. The model pore rejects alkali metal ions in the presence of biological concentrations of Ca2+ and predicts the blockade of alkali metal ion currents by micromolar Ca2+. Conductance patterns observed in varied mixtures containing Na+ and Li+, or Ba2+ and Ca2+, are predicted. Ca2+ is substantially more potent in blocking Na+ current than Ba2+. In apparent contrast to experiments using buffered Ca2+ solutions, the predicted potency of Ca2+ in blocking alkali metal ion currents depends on the species and concentration of the alkali metal ion, as is expected if these ions compete with Ca2+ for the pore. These experiments depend on the problematic estimation of Ca2+ activity in solutions buffered for Ca2+ and pH in a varying background of bulk salt. Simulations of Ca2+ distribution with the model pore bathed in solutions containing a varied amount of Li+ reveal a "barrier and well" pattern. The entry/exit barrier for Ca2+ is strongly modulated by the Li+ concentration of the bath, suggesting a physical explanation for observed kinetic phenomena. Our simulations show that the selectivity of L-type calcium channels can arise from an interplay of electrostatic and hard-core repulsion forces among ions and a few crucial channel atoms. The reduced system selects for the cation that delivers the largest charge in the smallest ion volume.

UR - http://www.scopus.com/inward/record.url?scp=66049090534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66049090534&partnerID=8YFLogxK

U2 - 10.1085/jgp.200910211

DO - 10.1085/jgp.200910211

M3 - Article

VL - 133

SP - 497

EP - 509

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 5

ER -