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Dezs Boda^1,2, Mónika Valiskó¹, Douglas Henderson², Bob Eisenberg³, Dirk Gillespie³, and Wolfgang Nonner⁴

¹ Department of Physical Chemistry, University of Pannonia, H-8201 Veszprém, Hungary
² Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602
³ Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL 60612
⁴ Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33101

Correspondence to Wolfgang Nonner: wnonner{at}med.miami.edu

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.

© 2009 Boda et al.
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