Molecular origin of VDAC selectivity towards inorganic ions: a combined molecular and Brownian dynamics study.

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.