Thermodynamics and Mechanism of the Membrane Permeation of Hv1 Channel Blockers.
Thermodynamics and Mechanism of the Membrane Permeation of Hv1 Channel Blockers.
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Hv1通道阻滞剂的膜渗透热力学及机制
DOI：
10.1007/s00232-020-00149-8
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Tobias DJ
中科院分区：
文献类型：
--
作者：
Lim VT;Freites JA;Tombola F;Tobias DJ
电压门控质子通道Hv 1介导质子从细胞流出。Hv 1整体上有助于各种生理过程，包括pH稳态和吞噬细胞的呼吸爆发。抑制Hv 1可能为治疗炎症性疾病、乳腺癌和缺血性脑损伤提供治疗途径。在这项工作中，我们研究了两个原型Hv 1抑制剂，2-胍基苯并咪唑（2GBI）和5-氯-2-胍基苯并咪唑（GBIC），从实验筛选类胍衍生物。两种化合物通过结合位于通道细胞内侧的相同位点来阻断质子传导。然而，当添加到细胞外介质中时，化合物在其抑制质子传导的能力方面存在很大差异，表明膜渗透性存在实质性差异。在这里，我们使用原子分子动力学模拟和自适应偏置力方法计算每种化合物渗透通过膜的平均力潜力。我们的研究结果合理化这两种阻滞剂之间的假定的区别就其渗透细胞膜的能力。
The voltage-gated proton channel Hv1 mediates efflux of protons from the cell. Hv1 integrally contributes to various physiological processes including pH homeostasis and the respiratory burst of phagocytes. Inhibition of Hv1 may provide therapeutic avenues for the treatment of inflammatory diseases, breast cancer, and ischemic brain damage. In this work, we investigate two prototypical Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and 5-chloro-2-guanidinobenzimidazole (GBIC), from an experimentally screened class of guanidine derivatives. Both compounds block proton conduction by binding the same site located on the intracellular side of the channel. However, when added to the extracellular medium, the compounds strongly differ in their ability to inhibit proton conduction, suggesting substantial differences in membrane permeability. Here, we compute the potential of mean force for each compound to permeate through the membrane using atomistic molecular dynamics simulations with the adaptive biasing force method. Our results rationalize the putative distinction between these two blockers with respect to their abilities to permeate the cellular membrane.
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