Edward Mendez-Otalvaro, Wojciech Kopec, Bert L de Groot
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引用次数: 0
Abstract
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.
TREK1是一种双孔域(2P)哺乳动物钾(K+)通道,可调节细胞膜上的静息电位,是治疗神经病变的一个很有前景的靶点。该通道的门控收敛于孔道最窄部分的构象:选择性滤波器(SF)。有多种假说可以解释 TREK1 的门控调节,包括连接 SF 与跨膜螺旋的环的动力学以及邻近 SF 的氢键(HB)网络的稳定性。最近,有报道称两种小分子(Q6F和Q5F)可作为激活剂,在单通道电流测量中通过增加其开放概率来影响TREK1。在此,我们利用分子动力学(MD)模拟研究了这些配体对之前提出的 TREK1 门控机制的影响。我们的研究结果表明,SF 上部区域的环路动力学与渗透事件/非渗透期仅表现出微弱的相关性,而 SF 后面的 HB 网络则表现出更强的相关性。这些非渗透期来自两种不同的机制:一种是 C 型失活(由 SF 顶部的扩张引起),这在之前已有描述;另一种是 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,配体还能通过调节羰基翻转的动态来提高渗透概率,而羰基翻转则受到 SF 底部一个苏氨酸残基的影响。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启示。
期刊介绍:
BJ publishes original articles, letters, and perspectives on important problems in modern biophysics. The papers should be written so as to be of interest to a broad community of biophysicists. BJ welcomes experimental studies that employ quantitative physical approaches for the study of biological systems, including or spanning scales from molecule to whole organism. Experimental studies of a purely descriptive or phenomenological nature, with no theoretical or mechanistic underpinning, are not appropriate for publication in BJ. Theoretical studies should offer new insights into the understanding ofexperimental results or suggest new experimentally testable hypotheses. Articles reporting significant methodological or technological advances, which have potential to open new areas of biophysical investigation, are also suitable for publication in BJ. Papers describing improvements in accuracy or speed of existing methods or extra detail within methods described previously are not suitable for BJ.