The Atomistic Details of the Ca2+ Permeation through the Open-State Ryanodine Receptor 1

Abstract

Ryanodine receptors (RyRs) are essential in the precise control of Ca2+ concentration in the cytosol by releasing Ca2+ from the sarco/endoplasmic reticulum. Several Cryo-EM structures of RyRs have been resolved, but the detailed Ca2+ permeation mechanism is still elusive. By using molecular dynamics (MD) simulations with a specially designed Ca2+ model that can quantitatively reproduce the interaction energies between Ca2+ and proteins, we found that multiple Ca2+ accumulate in the upper selectivity filter (SF) of the open-state RyR1, but only one Ca2+ can enter and translocate in the narrow SF at a time. The Ca2+ ions in the upper SF cannot enter the narrow SF without kicking out the Ca2+ in it. The Ca2+ is nearly fully hydrated during the permeation process. The Ca2+ binding sites and permeability obtained from our MD simulations are in good agreement with previous experimental results. Therefore, we propose a distant knock-on permeation mechanism for the hydrated Ca2+ ions through the RyR channels, which can explain the high permeability and low selectivity of the RyR channels.