Journal
BIOPHYSICAL JOURNAL
Volume 94, Issue 4, Pages 1169-1184Publisher
BIOPHYSICAL SOC
DOI: 10.1529/biophysj.107.116798
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Funding
- NIGMS NIH HHS [5-R01-GM076013, R01 GM076013] Funding Source: Medline
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A model of the ryanodine receptor (RyR) calcium channel is used to study the energetics of binding selectivity of Ca2+ versus monovalent cations. RyR is a calcium-selective channel with a DDDD locus in the selectivity filter, similar to the EEEE locus of the L-type calcium channel. While the affinity of RyR for Ca2+ is in the millimolar range (as opposed to the micromolar range of the L-type channel), the ease of single-channel measurements compared to L-type and its similar selectivity filter make RyR an excellent candidate for studying calcium selectivity. A Poisson-Nernst-Planck/density functional theory model of RyR is used to calculate the energetics of selectivity. Ca2+ versus monovalent selectivity is driven by the charge/space competition mechanism in which selectivity arises from a balance of electrostatics and the excluded volume of ions in the crowded selectivity filter. While electrostatic terms dominate the selectivity, the much smaller excluded-volume term also plays a substantial role. In the D4899N and D4938N mutations of RyR that are analyzed, substantial changes in specific components of the chemical potential profiles are found far from the mutation site. These changes result in the significant reduction of Ca2+ selectivity found in both theory and experiments.
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