TWIK-related potassium channel 1 (TREK1), a two-pore-domain mammalian potassium (K+) channel, regulates the resting potential across cell membranes, presenting a promising therapeutic target for neuropathy treatment. The gating of this channel converges in the conformation of the narrowest part of the pore: the selectivity filter (SF). Various hypotheses explain TREK1 gating modulation, including the dynamics of loops connecting the SF with transmembrane helices and the stability of hydrogen bond (HB) networks adjacent to the SF. Recently, two small molecules (Q6F and Q5F) were reported as activators that affect TREK1 by increasing its open probability in single-channel current measurements. Here, using molecular dynamics simulations, we investigate the effect of these ligands on the previously proposed modulation mechanisms of TREK1 gating compared to the apo channel. Our findings reveal that loop dynamics at the upper region of the SF exhibit only a weak correlation with permeation events/nonpermeation periods, whereas the HB network behind the SF appears more correlated. These nonpermeation periods arise from both distinct mechanisms: a C-type inactivation (resulting from dilation at the top of the SF), which has been described previously, and a carbonyl flipping in an SF binding site. We find that, besides the prevention of C-type inactivation in the channel, the ligands increase the probability of permeation by modulating the dynamics of the carbonyl flipping, influenced by a threonine residue at the bottom of the SF. These results offer insights for rational ligand design to optimize the gating modulation of TREK1 and related K+ channels.

中文翻译：

---

两种激活剂对 K2P 通道门控的影响


TWIK 相关钾通道 1 （TREK1） 是一种双孔结构域哺乳动物钾 （K+） 通道，可调节跨细胞膜的静息电位，为神经病变治疗提供了一个有前途的治疗靶点。该通道的门控收敛于孔隙最窄部分的构象：选择性过滤器 （SF）。各种假设解释了 TREK1 门控调节，包括将 SF 与跨膜螺旋连接的回路的动力学以及与 SF 相邻的氢键 （HB） 网络的稳定性。最近，据报道，两种小分子（Q6F 和 Q5F）作为激活剂，通过增加 TREK1 在单通道电流测量中的打开概率来影响 TREK1。在这里，使用分子动力学模拟，我们研究了这些配体对先前提出的 TREK1 门控调节机制与 apo 通道相比的影响。我们的研究结果表明，SF 上部区域的环动力学与渗透事件/非渗透期仅表现出较弱的相关性，而 SF 后面的 HB 网络似乎更相关。这些非渗透期由两种不同的机制产生：C 型失活（由 SF 顶部的扩张导致），如前所述，以及 SF 结合位点的羰基翻转。我们发现，除了防止通道中的 C 型失活外，配体还通过调节羰基翻转的动力学来增加渗透的可能性，受 SF 底部的苏氨酸残基影响。这些结果为合理的配体设计提供了见解，以优化 TREK1 和相关 K+ 通道的门控调节。