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Abstract：
The voltage-dependent anion channel (VDAC) serves as the major pore for metabolites and electrolytes in the outer mitochondrial membrane. To refine our understanding of ion permeation through this channel we performed an extensive Brownian (BD) and molecular dynamics (MD) study on the mouse VDAC isoform 1 wild-type and mutants (K20E, D30K, K61E, E158K and K252E). The selectivity and the conductance of the wild-type and of the variant channels computed from the BD trajectories are in agreement with experimental data. The calculated selectivity is shown to be very sensitive to slight conformational changes which may have some bearing on the variability of the selectivity values measured on the VDAC open state. The MD and BD free energy profiles of the ion permeation suggest that the pore region comprising the N-terminal helix and the barrel band encircling it predominantly controls the ion transport across the channel. The overall 12μs BD and 0.9μs MD trajectories of the mouse VDAC isoform 1 wild-type and mutants feature no distinct pathways for ion diffusion and no long-lived ion-protein interactions. The dependence of ion distribution in the wild-type channel with the salt concentration can be explained by an ionic screening of the permanent charges of the protein arising from the pore. Altogether these results bolster the role of electrostatic features of the pore as the main determinant of VDAC selectivity towards inorganic anions.
摘要：
电压依赖性阴离子通道（VDAC）是线粒体外膜中代谢物和电解质的主要孔。为了完善我们对通过该通道的离子渗透的理解，我们对小鼠VDAC亚型1野生型和突变体（K20E，D30K,K61E,E158K和K252E）。从BD轨迹计算的野生型和变种通道的选择性和电导与实验数据一致。计算出的选择性对轻微的构象变化非常敏感，这可能对在VDAC开放状态下测得的选择性值的可变性有一定影响。离子渗透的MD和BD自由能曲线表明，包含N末端螺旋和环绕其的桶带的孔区域主要控制离子穿过通道的传输。小鼠VDAC同种型1野生型和突变体的总体12μsBD和0.9μsMD轨迹没有明显的离子扩散途径，也没有长寿命的离子-蛋白质相互作用。野生型通道中离子分布与盐浓度的依赖性可以通过对孔中产生的蛋白质的永久电荷进行离子筛选来解释。总之，这些结果支持了孔的静电特征作为VDAC对无机阴离子的选择性的主要决定因素的作用。
