Abstract
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.
Highlights
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
There are six adjustable parameters, including bCD, QC, εC, σC, εD, and σD, where bCD is the distance between dummy atoms and the central atom, QC is the charge on the central atom, and ε and σ are the LJ parameters of the central (C) and dummy (D) atoms, respectively
The multi-site ion model cannot explicitly represent the charge transfer and polarization effect, the simulation results showed that our new model behaves much better than conventional single-point ion models
Summary
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. To study the detailed interactions between ions and proteins, we can often use molecular dynamics (MD) simulations to provide microscopic and quantitative insights, thereby obtaining the specific functional mechanisms of the relevant proteins[3,4,5,6]. Kohagen et al proposed to scale the partial charges on the Ca2+ to account for the charge transfer and polarization[22,23] Another strategy is to represent an ion by distributing electrostatic and Lennard-Jones (LJ) interactions on multiple sites, which can introduce a much larger parameter space and make the ion model more tailorable[24,25,26]. In the present work, we developed a new multi-site Ca2+ model optimized for Ca2+-protein interaction (inset of Fig. 1), and utilize this model to study the detailed Ca2+ permeation mechanism through the RyR1 channel, which showed distinct features from the widely studied K+ and Na+ channels
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