The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles. A deep understanding of the complex Ca²⁺‐activation/inhibition mechanism of RyRs requires detailed structural and dynamic information for RyRs in different functional states (eg, with Ca²⁺ bound to activating or inhibitory sites). Recently, high‐resolution structures of the RyR isoform 1 (RyR1) were solved by cryo‐electron microscopy, revealing the location of a Ca²⁺ binding site for activation. Toward elucidating the Ca²⁺‐modulation mechanism of RyR1, we performed extensive molecular dynamics simulation of the core RyR1 structure in the presence and absence of activating and solvent Ca²⁺ (total simulation time is >5 μs). In the presence of solvent Ca²⁺, Ca²⁺ binding to the activating site enhanced dynamics of RyR1 with higher inter‐subunit flexibility, asymmetric inter‐subunit motions, outward domain motions and partial pore dilation, which may prime RyR1 for subsequent channel opening. In contrast, the solvent Ca²⁺ alone reduced dynamics of RyR1 and led to inward domain motions and pore contraction, which may cause inhibition. Combining our simulation with the map of disease mutation sites in RyR1, we constructed a wiring diagram of key domains coupled via specific hydrogen bonds involving the mutation sites, some of which were modulated by Ca²⁺ binding. The structural and dynamic information gained from this study will inform future mutational and functional studies of RyR1 activation and inhibition by Ca²⁺.

中文翻译：

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通过分子动力学模拟研究ryanodine受体1的双重Ca2 +调节。

ryanodine受体（RyR）对于横纹肌中的钙信号传导至关重要。对RyRs复杂的Ca ²⁺激活/抑制机制的深入了解，需要针对不同功能状态下RyRs的详细结构和动态信息（例如，Ca ²⁺与激活或抑制位点结合）。最近，RyR亚型1（RyR1）的高分辨率结构通过冷冻电子显微镜得以解决，揭示了激活的Ca ²⁺结合位点的位置。为了阐明RyR1的Ca ²⁺调节机制，我们在存在和不存在活化和溶剂Ca ^2+的情况下，对核心RyR1结构进行了广泛的分子动力学模拟（总仿真时间> 5μs）。在存在溶剂Ca ²⁺的情况下，Ca ²⁺与活化位点的结合增强了RyR1的动力学，具有更高的亚基间柔性，不对称的亚基间运动，向外域运动和部分孔扩张，这可能会引发RyR1用于随后的通道开放。相反，单独使用溶剂Ca ^2+会降低RyR1的动力学并导致向内域运动和孔收缩，这可能引起抑制。将我们的模拟与RyR1中疾病突变位点的图谱相结合，我们构建了通过涉及突变位点的特定氢键偶联的关键域的布线图，其中一些由Ca ²⁺调节捆绑。从这项研究中获得的结构和动态信息将为将来的RyR1激活和Ca ²⁺抑制的突变和功能研究提供参考。