Mendez-Otalvaro Edward, Kopec Wojciech, de Groot Bert L
Computational Biomolecular Dynamics Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Computational Biomolecular Dynamics Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany; Department of Chemistry, Queen Mary University of London, London, United Kingdom.
Biophys J. 2024 Oct 1;123(19):3408-3420. doi: 10.1016/j.bpj.2024.08.006. Epub 2024 Aug 19.
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.
TWIK相关钾通道1（TREK1）是一种双孔结构域的哺乳动物钾（K）通道，可调节细胞膜的静息电位，是神经病变治疗中一个很有前景的治疗靶点。该通道的门控作用集中在孔最窄部分的构象上：选择性过滤器（SF）。有各种假说来解释TREK1的门控调节，包括连接SF与跨膜螺旋的环的动力学以及SF附近氢键（HB）网络的稳定性。最近，有报道称两种小分子（Q6F和Q5F）作为激活剂，在单通道电流测量中通过增加TREK1的开放概率来影响它。在这里，我们使用分子动力学模拟，研究了这些配体与无配体通道相比，对先前提出的TREK1门控调节机制的影响。我们的研究结果表明，SF上部区域的环动力学与通透事件/非通透期仅表现出弱相关性，而SF后面的HB网络似乎相关性更强。这些非通透期源于两种不同的机制：一种是之前描述过的C型失活（由SF顶部的扩张引起），另一种是SF结合位点中的羰基翻转。我们发现，除了防止通道中的C型失活外，这些配体还通过调节羰基翻转的动力学来增加通透概率，而羰基翻转的动力学受SF底部的一个苏氨酸残基影响。这些结果为合理设计配体以优化TREK1和相关K通道的门控调节提供了见解。
