Deng Jiahua, Cui Qiang
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
Department of Physics, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
J Phys Chem Lett. 2024 Jul 25;15(29):7436-7441. doi: 10.1021/acs.jpclett.4c01359. Epub 2024 Jul 15.
In the hydrophobic gating mechanism proposed for some ion channels, ion permeation is not blocked by the physical dimension of the channel pore but by its dewetted state which constitutes the energetic bottleneck. A major source of uncertainty in the mechanism is that the dewetted state was not observed in experiments and only probed in simulations using nonpolarizable force fields, which do not accurately represent the properties of confined water. Here we analyze hydration of the central cavity in the pore-gate domain of the Big Potassium channel using molecular dynamics and grand canonical Monte Carlo simulations with enhanced sampling techniques. Including polarization leads to a much drier dewetted state and a higher barrier for the transition to the wet state, suggesting more effective hydrophobic gating. The simulations also identify two backbone carbonyls at the bottom of the selectivity filter as good candidates for characterizing the dewetted state using infrared spectroscopies.
在为某些离子通道提出的疏水门控机制中，离子渗透并非被通道孔的物理尺寸所阻挡，而是被其构成能量瓶颈的去湿状态所阻挡。该机制中一个主要的不确定来源是，去湿状态在实验中未被观察到，仅在使用非极化力场的模拟中进行了探测，而非极化力场无法准确表征受限水的性质。在此，我们使用分子动力学和具有增强采样技术的巨正则蒙特卡罗模拟，分析了大钾通道孔门区域中心腔的水合作用。纳入极化会导致去湿状态更加干燥，且向湿润状态转变的能垒更高，这表明疏水门控更有效。模拟还确定了选择性过滤器底部的两个主链羰基，它们是使用红外光谱表征去湿状态的良好候选者。
