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

Ryanodine receptors (RyRs) are ion channels responsible for the fast release of Ca 2+ from the sarco/endoplasmic reticulum to the cytosol and show a selectivity of Ca 2+ over monovalent cations. By utilizing a recently developed multisite Ca 2+ 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 Ca 2+ make it preferable to K + in competition for space in this confined region of negative electrostatic potential. The presence of Ca 2+ in the upper selectivity filter significantly increases the energy barrier of K + permeation, while the presence of K + has little impact on the Ca 2+ 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 Ca 2+ release function. The mechanism could be utilized in protein- and nanoengineering for valence selectivity of ion species.