Department of Mechanical and Aerospace Engineering, Shiraz University of Technology, Shiraz, Iran.
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.
Sci Rep. 2022 Jun 15;12(1):9976. doi: 10.1038/s41598-022-14446-w.
Mechanosensitive (MS) ion channels are primary transducers of mechanical force into electrical and/or chemical intracellular signals. Many diverse MS channel families have been shown to respond to membrane forces. As a result of this intimate relationship with the membrane and proximal lipids, amphipathic compounds exert significant effects on the gating of MS channels. Here, we performed all-atom molecular dynamics (MD) simulations and employed patch-clamp recording to investigate the effect of two amphipaths, Fluorouracil (5-FU) a chemotherapy agent, and the anaesthetic trifluoroethanol (TFE) on structurally distinct mechanosensitive channels. We show that these amphipaths have a profound effect on the bilayer order parameter as well as transbilayer pressure profile. We used bacterial mechanosensitive channels (MscL/MscS) and a eukaryotic mechanosensitive channel (TREK-1) as force-from-lipids reporters and showed that these amphipaths have differential effects on these channels depending on the amphipaths' size and shape as well as which leaflet of the bilayer they incorporate into. 5-FU is more asymmetric in shape and size than TFE and does not penetrate as deep within the bilayer as TFE. Thereby, 5-FU has a more profound effect on the bilayer and channel activity than TFE at much lower concentrations. We postulate that asymmetric effects of amphipathic molecules on mechanosensitive membrane proteins through the bilayer represents a general regulatory mechanism for these proteins.
机械敏感 (MS) 离子通道是将机械力转化为电和/或化学细胞内信号的主要传感器。许多不同的 MS 通道家族已被证明对膜力有反应。由于与膜和临近脂质的这种密切关系，两亲化合物对 MS 通道的门控产生显著影响。在这里，我们进行了全原子分子动力学 (MD) 模拟，并采用膜片钳记录来研究两种两亲化合物氟尿嘧啶 (5-FU)（一种化疗药物）和麻醉剂三氟乙醇 (TFE) 对结构上不同的机械敏感通道的影响。我们表明，这些两亲化合物对双层有序参数和跨双层压力分布有深远的影响。我们使用细菌机械敏感通道 (MscL/MscS) 和真核机械敏感通道 (TREK-1) 作为从脂质产生力的报告器，并表明这些两亲化合物根据其大小和形状以及它们整合到双层的哪一侧，对这些通道有不同的影响。5-FU 的形状和大小比 TFE 更不对称，并且不会像 TFE 那样深入双层。因此，5-FU 在低得多的浓度下对双层和通道活性的影响比 TFE 更深远。我们假设，两亲分子通过双层对机械敏感膜蛋白的不对称影响代表了这些蛋白质的一种普遍调节机制。
