Ryanodine receptors (RyR) are ion channels responsible for the release of Ca2+ from the sarco/endoplasmic reticulum and play a crucial role in the precise control of Ca2+ concentration in the cytosol. The detailed permeation mechanism of Ca2+ through RyR is still elusive. By using molecular dynamics simulations with a specially designed Ca2+ model, we show that multiple Ca2+ ions accumulate in the upper selectivity filter of RyR1, but only one Ca2+ can occupy and translocate in the narrow pore at a time, assisted by electrostatic repulsion from the Ca2+ within the upper selectivity filter. The Ca2+ is nearly fully hydrated with the first solvation shell intact during the whole permeation process. These results suggest a remote knock-on permeation mechanism and one-at-a-time occupation pattern for the hydrated Ca2+ within the narrow pore, uncovering the basis underlying the high permeability and low selectivity of the RyR channels.

中文翻译：

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多部位离子模型揭示了ryanodine受体的Ca2 +渗透机制。

Ryanodine受体（RyR）是负责从肌膜/内质网释放Ca2 +的离子通道，在精确控制细胞溶质中Ca2 +的浓度中起着至关重要的作用。Ca2 +通过RyR的详细渗透机制仍然难以捉摸。通过使用带有专门设计的Ca2 +模型的分子动力学模拟，我们发现RyR1的上选择性过滤器中积累了多个Ca2 +离子，但是一次只有一个Ca2 +可以在狭窄的孔中占据并迁移，这是由于Ca2 +产生的静电排斥作用所致在上选择性过滤器中。在整个渗透过程中，Ca2 +几乎完全水合，第一个溶剂化壳完好无损。这些结果表明，狭窄孔隙中水合Ca2 +的远程连锁渗透机制和一次性占用模式，