基于AMOEBA可极化力场研究蛋白二聚化对于gramicidin A通道电导的影响

在离子通道性质的研究中，由于可极化力场计算量巨大，长期以来使用最广泛的依旧是经典力场. 本文考察了可极化力场在描述离子通道gramicidin A(gA)二聚状态下离子输运性质方面的可靠性. 利用AMOEBA可极化力场对单通道gA和双通道gA进行增强采样模拟，从电导、扩散系数和自由能等方面描述了gA二聚化对钾离子和钠离子穿越通道过程的影响. 计算结果显示，可极化力场模拟获得的钾离子和钠离子穿越通道的电导与实验数值吻合. 进一步的数据分析揭示了蛋白质二聚化影响gA通道离子输运性质的分子机制，即蛋白二聚化通过调整gA蛋白周围的环境(磷脂头基、通道外离子和体相水分子的分布)而不是直接调整gA蛋白的构象来加速钾离子和钠离子穿越通道.

Effect of Protein Dimerization on Ion Conductivity of Gramicidin A Channel Studied Using Polarizable Force Field

In studies of ion channel systems, due to the huge computational cost of polarizable force fields, classical force fields remain the most widely used for a long time. In this work, we used the AMOEBA polarizable atomic multipole force field in enhanced sampling simula-tions of single-channel gramicidin A (gA) and double-channel gA systems and investigated its reliability in characterizing ion-transport properties of the gA ion channel under dimer-ization. The influence of gA dimerization on the permeation of potassium and sodium ions through the channel was described in terms of conductance, diffusion coefficient, and free energy profile. Results from the polarizable force field simulations show that the conductance of potassium and sodium ions passing through the single- and double-channel agrees well with experimental values. Further data analysis reveals that the molecular mechanism of protein dimerization affects the ion-transport properties of gA channels, i.e., protein dimer- ization accelerates the permeation of potassium and sodium ions passing through the double-channel by adjusting the environment around gA protein (the distribution of phospholipid head groups, ions outside the channel, and bulk water), rather than directly adjusting the conformation of gA protein.