Department of Physics , Zhejiang Normal University , Jinhua 321004 , China.
Department of Physics , Indiana University Purdue University Indianapolis , 402 North Blackford Street , Indianapolis , Indiana 46202 , United States.
J Chem Inf Model. 2019 Feb 25;59(2):777-785. doi: 10.1021/acs.jcim.8b00914. Epub 2019 Feb 13.
Permeability and conductance are the major transport properties of membrane channels, quantifying the rate of channel crossing by the solute. It is highly desirable to calculate these quantities in all-atom molecular dynamics simulations. When the solute crossing rate is low, however, direct methods would require prohibitively long simulations, and one thus typically adopts alternative strategies based on the free energy of single solute along the channel. Here we present a new method to calculate the crossing rate by initiating unbiased trajectories in which the solute is released at the free energy barrier. In this method, the total time the solute spends in the barrier region during a channel crossing (transition path) is used to determine the kinetic rate. Our method achieves a significantly higher statistical accuracy than the classical reactive flux method, especially for diffusive barrier crossing. Our test on ion permeation through a carbon nanotube verifies that the method correctly predicts the crossing rate and reproduces the spontaneous crossing events as in long equilibrium simulations. The rigorous and efficient method here will be valuable for quantitatively connecting simulations to experimental measurement of membrane channels.
通透性和传导性是膜通道的主要传输特性，它们定量描述了溶质通过通道的速度。在全原子分子动力学模拟中，计算这些参数是非常理想的。然而，当溶质的穿越速率较低时，直接方法需要进行极长的模拟，因此人们通常采用基于通道中单个溶质自由能的替代策略。在这里，我们提出了一种新的方法，通过在溶质释放到自由能势垒的无偏轨迹中，来计算穿越速率。在这种方法中，溶质在通道穿越（过渡路径）过程中在势垒区域内花费的总时间用于确定动力学速率。与经典的反应通量法相比，我们的方法具有更高的统计精度，特别是对于扩散势垒穿越。我们通过碳纳米管中的离子渗透测试验证了该方法能够正确预测穿越速率，并重现了长平衡模拟中自发的穿越事件。这里提出的严格而高效的方法对于将模拟与膜通道的实验测量定量联系起来将是非常有价值的。
