Probing the energy landscape of activation gating of the bacterial potassium channel KcsA.
Probing the energy landscape of activation gating of the bacterial potassium channel KcsA.
复制标题
DOI：
10.1371/journal.pcbi.1003058
复制
发表时间：
2013
影响因子：
4.3
通讯作者：
Stary-Weinzinger A
中科院分区：
文献类型：
--
作者：
Linder T;de Groot BL;Stary-Weinzinger A
细菌钾离子通道KcsA具有多种构象，是研究离子通道激活门控的理想模型。在这项研究中，基本的动力学模拟应用于获得洞察的过渡途径和能量分布的KcsA孔门控。与先前的假设一致，我们的模拟揭示了两个阶段的激活门控过程。在第一阶段中，观察到TM2中的局部结构重排，导致中间通道构象，随后是大的结构重排，导致KcsA完全开放。高度保守的苯丙氨酸，F114，在束交叉区的构象变化是至关重要的从一个封闭的过渡到一个中间状态。3.9µs伞形采样计算表明，有两个定义明确的能量势垒划分封闭，中间和开放通道状态。与突变研究一致，发现封闭状态比开放状态在能量上更有利。此外，模拟提供了新的见解F103之间的激活门和选择性过滤器的动态耦合效应。对单个亚基的研究支持激活门控过程中亚基的协同性。电压门控离子通道是膜包埋的蛋白质，其在膜电位变化时启动电信号。这些通道参与生物关键过程，如神经冲动的产生和传播。突变可能导致严重的疾病，如心律失常，糖尿病或偏头痛，使它们成为重要的药物靶点。离子通道的活性由动态构象变化控制，动态构象变化调节通过中心孔的离子流。这个过程，涉及打开和关闭的渠道，被称为门控。为了完全理解或控制离子通道门控，我们需要解开基本原理。晶体结构，特别是K+通道，提供了很好的洞察不同的通道状态的构象。然而，过渡态和结构重排仍然是未知的。在这里，我们使用分子动力学模拟来模拟门控的完整过渡途径和能量景观。我们的研究结果表明，通道门控涉及局部结构的变化，其次是全球构象的变化。在我们的模拟中确定的许多残基的重要性得到了实验研究的支持。准确模拟离子通道门控跃迁的能力可能有助于更好地理解离子通道相关疾病和药物开发。
The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 µs umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating. Voltage gated ion channels are membrane embedded proteins that initiate electrical signaling upon changes in membrane potential. These channels are involved in biological key processes such as generation and propagation of nerve impulses. Mutations may lead to serious diseases such as cardiac arrhythmia, diabetes or migraines, rendering them important drug targets. The activity of ion channels is controlled by dynamic conformational changes that regulate ion flow through a central pore. This process, which involves opening and closing of the channels, is known as gating. To fully understand or to control ion channel gating, we need to unravel the underlying principles. Crystal structures, especially of K+ channels, have provided excellent insights into the conformation of different channel states. However, the transition states and structural rearrangements are still unknown. Here we use molecular dynamics simulations to simulate the full transition pathway and energy landscape of gating. Our results suggest that channel gating involves local structural changes followed by global conformational changes. The importance of many of the residues identified in our simulations is supported by experimental studies. The ability to accurately simulate the gating transitions of ion channels may be beneficial for a better understanding of ion channel related diseases and drug development.
登录
查看更多内容
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
2.9
作者：
Denning, Elizabeth J.;Woolf, Thomas B.
通讯作者：
Woolf, Thomas B.
影响因子：
4.4
作者：
Compoint, M;Picaud, F;Girardet, C
通讯作者：
Girardet, C
影响因子：
64.8
作者：
通讯作者：
--