Energetics of Glutamate Binding to an Ionotropic Glutamate Receptor,The Journal of Physical Chemistry B

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Energetics of Glutamate Binding to an Ionotropic Glutamate Receptor
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.jpcb.7b06862
Alvin Yu _{1,

2} , Albert Y. Lau _{1,

2}

Affiliation

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are responsible for the majority of excitatory transmission at the synaptic cleft. Mechanically speaking, agonist binding to the ligand binding domain (LBD) activates the receptor by triggering a conformational change that is transmitted to the transmembrane region, opening the ion channel pore. We use fully atomistic molecular dynamics simulations to investigate the binding process in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, an iGluR subtype. The string method with swarms of trajectories was applied to calculate the possible pathways glutamate traverses during ligand binding. Residues peripheral to the binding cleft are found to metastably bind the ligand prior to ligand entry into the binding pocket. Umbrella sampling simulations were performed to compute the free energy barriers along the binding pathways. The calculated free energy profiles demonstrate that metastable interactions contribute substantially to the energetics of ligand binding and form local minima in the overall free energy landscape. Protein–ligand interactions at sites outside of the orthosteric agonist-binding site may serve to lower the transition barriers of the binding process.

中文翻译：

谷氨酸与离子型谷氨酸受体结合的能量学

离子型谷氨酸受体（iGluRs）是配体门控的离子通道，负责突触间隙处的大多数兴奋性传递。从机械上讲，与配体结合域（LBD）结合的激动剂通过触发构象变化激活受体，该构象变化传递至跨膜区域，从而打开离子通道孔。我们使用完全原子分子动力学模拟来研究iGluR亚型α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体中的结合过程。应用具有轨迹轨迹的弦方法来计算配体结合过程中谷氨酸遍历的可能途径。发现在结合裂隙外围的残基在配体进入结合口袋之前可稳定地结合配体。进行了伞采样模拟，以计算沿结合途径的自由能垒。计算出的自由能曲线表明，亚稳态相互作用在很大程度上促进了配体结合的能量，并在整个自由能格局中形成了局部极小值。在正构激动剂结合位点之外的位点的蛋白质-配体相互作用可能有助于降低结合过程的过渡障碍。

更新日期：2017-11-09

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