The Journal of Membrane Biology ( IF 2.3 ) Pub Date : 2020-11-16 , DOI: 10.1007/s00232-020-00149-8 Victoria T Lim 1 , J Alfredo Freites 1 , Francesco Tombola 2, 3 , Douglas J Tobias 1, 3
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Abstract
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.
Graphic Abstract
中文翻译：
Hv1 通道阻滞剂膜渗透的热力学和机理
摘要
电压门控质子通道 Hv1 介导质子从细胞中流出。Hv1 整体有助于各种生理过程，包括 pH 稳态和吞噬细胞的呼吸爆发。Hv1的抑制可能为炎症性疾病、乳腺癌和缺血性脑损伤的治疗提供治疗途径。在这项工作中，我们从实验筛选的一类胍衍生物中研究了两种原型 Hv1 抑制剂，2-胍基苯并咪唑 (2GBI) 和 5-氯-2-胍基苯并咪唑 (GBIC)。两种化合物都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，这些化合物在抑制质子传导的能力方面存在很大差异，这表明膜通透性存在显着差异。这里，我们使用具有自适应偏置力方法的原子分子动力学模拟来计算每种化合物渗透通过膜的平均力的潜力。我们的结果合理化了这两种阻滞剂在渗透细胞膜能力方面的假定区别。
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