Department of Chemistry, Universidad Autónoma de Madrid, Calle Francisco Tomás y Valiente, 7, 28049, Madrid, Spain.
Phys Chem Chem Phys. 2021 Feb 7;23(5):3552-3564. doi: 10.1039/d0cp06140a. Epub 2021 Jan 29.
The activity of voltage-gated ion channels can be controlled by the binding of photoswitches inside their internal cavity and subsequent light irradiation. We investigated the binding of azobenzene and p-diaminoazobenzene to the human Na1.4 channel in the inactivated state by means of Gaussian accelerated molecular dynamics simulations and free-energy computations. Three stable binding pockets were identified for each of the two photoswitches. In all the cases, the binding is controlled by the balance between the favorable hydrophobic interactions of the ligands with the nonpolar residues of the protein and the unfavorable polar solvation energy. In addition, electrostatic interactions between the ligand and the polar aminoacids are also relevant for p-diaminoazobenzene due to the presence of the amino groups on the benzene moieties. These groups participate in hydrogen bonding in the most favorable binding pocket and in long-range electrostatic interactions in the other pockets. The thermodinamically preferred binding sites found for both photoswitches are close to the selectivity filter of the channel. Therefore, it is very likely that the binding of these ligands will induce alterations in the ion conduction through the channel.
电压门控离子通道的活性可以通过其内部腔室中光开关的结合和随后的光照射来控制。我们通过高斯加速分子动力学模拟和自由能计算研究了偶氮苯和对二氨基偶氮苯与人源 Na1.4 通道在失活状态下的结合。两种光开关都确定了三个稳定的结合口袋。在所有情况下，配体与蛋白质的非极性残基之间有利的疏水相互作用与不利的极性溶剂化能之间的平衡控制了结合。此外，由于苯环部分上存在氨基，配体与极性氨基酸之间的静电相互作用对于对二氨基偶氮苯也很重要。这些基团在最有利的结合口袋中参与氢键形成，在其他口袋中参与远程静电相互作用。对于两种光开关都发现的热力学上优先的结合位点接近通道的选择性过滤器。因此，这些配体的结合很可能会引起离子通过通道的传导发生改变。
