Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter.
Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter.
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DOI：
10.1038/s41598-017-00256-y
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发表时间：
2017-04-04
影响因子：
4.6
通讯作者：
Pande VS
中科院分区：
文献类型：
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作者：
Harrigan MP;McKiernan KA;Shanmugasundaram V;Denny RA;Pande VS
双孔结构域钾（K2 P）通道离子电导受直接或间接门控通道选择性过滤器（SF）的各种刺激调节。最近的晶体结构的TREK-2成员的K2 P家族揭示了不同的“向上”和“向下”的状态，通过机械拉伸激活过程中假设。我们对TREK-2通道进行了195 μs的全原子无偏分子动力学模拟，以探索膜拉伸如何调节SF门。马尔可夫模型揭示了一种新的“捏”SF配置，拉伸激活迅速不稳定。自由能势垒高度计算的关键步骤中的传导途径表明，这种捏状态损害离子传导。我们的模拟预测，这种低电导状态是专门访问的压缩，“向下”的构象，其中细胞内的螺旋排列变构捏SF。通过明确地将结构与功能联系起来，我们对不断发展的K2 P难题做出了重要的理解。
Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.