Atomistic Details of Charge/Space Competition in the Ca2+ Selectivity of Ryanodine Receptors

Abstract

Ryanodine receptors (RyRs) are ion channels responsible for the fast release of Ca²⁺ from the sarco/endoplasmic reticulum to the cytosol and show a selectivity of Ca²⁺ over monovalent cations. By utilizing a recently developed multisite Ca²⁺ model in molecular dynamic simulations, we show that multiple cations accumulate in the upper selectivity filter of RyRs, and the small size and high valence of Ca²⁺ make it preferable to K⁺ in competition for space in this confined region of negative electrostatic potential. The presence of Ca²⁺ in the upper selectivity filter significantly increases the energy barrier of K⁺ permeation, while the presence of K⁺ has little impact on the Ca²⁺ permeation. Our results provide the atomistic details of the charge/space competition mechanism for the ion selectivity of RyRs, which ensures the robustness of their Ca²⁺ release function. The mechanism could be utilized in protein- and nanoengineering for valence selectivity of ion species.