<br>谷氨酸受体离子通道钙渗透机制,Journal of Chemical Information and Modeling

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谷氨酸受体离子通道钙渗透机制
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-02-09 , DOI: 10.1021/acs.jcim.2c01494
Florian Karl Schackert _{1,

2} , Johann Biedermann _{3,

4} , Saeid Abdolvand _{3,

4} , Sonja Minniberger _{3,

4} , Chen Song _{5,

6} , Andrew J R Plested _{3,

4} , Paolo Carloni _{1,

2} , Han Sun _{4,

7}

Affiliation

α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 是神经递质激活的阳离子通道，在脊椎动物大脑中普遍表达。 RNA 编辑对通过通道孔的钙流量的调节与突触可塑性有关，而过量的钙流入会带来神经退行性变的风险。不幸的是，这一关键过程背后的分子机制大多未知。在这里，我们使用分子动力学 (MD) 模拟以及最近引入的 Ca ²⁺多位点力场参数研究了钙渗透性 AMPAR 中的钙传导。我们的计算与实验一致，并解释了不同 RNA 编辑形式的 GluA2 中不同的钙渗透性。对于其中一个已识别的金属结合位点，多尺度量子力学/分子力学 (QM/MM) 模拟进一步验证了 MD 的结果，并揭示了金属离子与其第一个溶剂化壳之间的小但可重复的电荷转移。此外，MD 模拟得出的离子占据独立地再现了模拟 AMPAR 选择性滤光片的 NaK 通道的 X 射线结构中的 Ca ²⁺结合剖面。这项综合研究包括 X 射线晶体学、多位点 MD 和多尺度 QM/MM 模拟，为 AMPAR 中的 Ca ²⁺渗透机制提供了前所未有的见解，并为研究 Ca ²⁺发挥关键作用的其他生物过程铺平了道路。

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Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are neurotransmitter-activated cation channels ubiquitously expressed in vertebrate brains. The regulation of calcium flux through the channel pore by RNA-editing is linked to synaptic plasticity while excessive calcium influx poses a risk for neurodegeneration. Unfortunately, the molecular mechanisms underlying this key process are mostly unknown. Here, we investigated calcium conduction in calcium-permeable AMPAR using Molecular Dynamics (MD) simulations with recently introduced multisite force-field parameters for Ca²⁺. Our calculations are consistent with experiment and explain the distinct calcium permeability in different RNA-edited forms of GluA2. For one of the identified metal binding sites, multiscale Quantum Mechanics/Molecular Mechanics (QM/MM) simulations further validated the results from MD and revealed small but reproducible charge transfer between the metal ion and its first solvation shell. In addition, the ion occupancy derived from MD simulations independently reproduced the Ca²⁺ binding profile in an X-ray structure of an NaK channel mimicking the AMPAR selectivity filter. This integrated study comprising X-ray crystallography, multisite MD, and multiscale QM/MM simulations provides unprecedented insights into Ca²⁺ permeation mechanisms in AMPARs, and paves the way for studying other biological processes in which Ca²⁺ plays a pivotal role.

更新日期：2023-02-09

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