BK钾通道中脂质介导的疏水性门控
Lipid-mediated hydrophobic gating in the BK potassium channel
AI总结：
本研究通过分子模拟与自由能计算揭示BK通道中环形脂质进入孔道窗孔、诱导蒸汽泡形成的疏水门控机制，并解释Ca²⁺调控及阻断剂可及性实验。
摘要：
大电导钙激活钾（BK）通道缺少大多数6TM家族离子通道所具有的典型胞内侧束交叉门。这一观察最初由无Ca²⁺条件下的孔道可及性实验推断，最近又得到非导电状态冷冻电镜结构的证实，并引出一个令人困惑的问题：在没有空间位阻的情况下，门控如何发生？为回答该问题，我们开展了分子模拟和精确自由能计算，以获得从无Ca²⁺状态开始、在Ca²⁺结合后导致离子导电这一事件序列的微观图像。结果揭示了环形脂质出人意料的作用：它们实际上是门控机制不可分割的组成部分。由于窗孔结构的存在，“关闭”的无Ca²⁺孔道可被脂质烷基链的甲基占据。这种动态占据会触发并稳定内腔中蒸汽泡的成核，从而阻碍离子导电。相比之下，Ca²⁺结合会使这些脂质移出内腔，降低该区域疏水性，进而使孔道水合并允许导电。这种脂质介导的疏水性门控合理解释了若干看似存在矛盾的实验观察，包括阻断剂依赖于状态的孔道可及性。
英文摘要：
The large-conductance, calcium-activated potassium (BK) channel lacks the typical intracellular bundle-crossing gate present in most ion channels of the 6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore accessibility experiments and recently corroborated by a CryoEM structure of the non-conductive state, raises a puzzling question: how can gating occur in absence of steric hindrance? To answer this question, we carried out molecular simulations and accurate free energy calculations to obtain a microscopic picture of the sequence of events that, starting from a Ca$^{2+}$-free state leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an unexpected role for annular lipids, which turn out to be an integral part of the gating machinery. Due to the presence of fenestrations, the "closed" Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl chains. This dynamic occupancy triggers and stabilizes the nucleation of a vapor bubble into the inner pore cavity, thus hindering ion conduction. By contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside the inner cavity, lowering the hydrophobicity of this region and thus allowing for pore hydration and conduction. This lipid-mediated hydrophobic gating rationalizes several seemingly problematic experimental observations, including the state-dependent pore accessibility of blockers.
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