Abstract
Voltage dependent anion channel (VDAC) is the pore-forming protein of outer mitochondrial membrane. In mammals three isoforms exist: VDAC1, VDAC2, VDAC3 (1). The VDAC1 is the most abundant (2) and studied isoform, the only one whose 3D structure was solved at high resolution. All-atom MD simulations (∼1 μs each) were used to compare the open-state of the three human isoforms, obtaining a structural characterization particularly focused on the localization and mobility of N-termini (3) and its interaction with the β-barrel. In addition, each isoform was simulated in presence of KCl 0.5 M to investigate ions diffusion events, either in absence and presence of a 10 mV external electric field, in order to compare the selectivity, permeability ratio and ion currents.The specific hydrophobic interactions and hydrogen bonds between N-terminal fragments and the barrel were found to be related to the intrinsic breathing motions of the latter. The overall shape of channels can be described as an ellipse, whose axes fluctuations are markedly anticorrelated in hVDAC1 and hVDAC3 while, essentially, no correlation was observed in hVDAC2.Free-energy profiles of chloride and potassium ions reflect the anion selectivity of the isoforms with no significant differences in the average translocation time in both directions. However, a comprehensive explanation of differences between chloride and potassium was obtained with the cluster analysis that showed a preferential localization of the former in the middle of the pore while the latter 'segregated' at the periphery. The relative number of clusters in the three human isoforms of VDAC agrees with their relative selectivity. The position of the clusters matches with the charged residues distribution around the lumen.1. Messina A. (2012) BBA 181:1466.2. De Pinto V. (2010) BBA 1797:1268.3. Reina S. (2010) FEBS Lett. 584:2837.
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