A computational study of ion current modulation in hVDAC3 induced by disulfide bonds.

摘要: The human VDAC channel exists in three isoforms characterized by high sequence homology and structural similarity. Yet the function mode of action hVDAC3 are still elusive. presence six surface cysteines exposed to oxidizing environment mitochondrial inter-membrane space suggests possible establishment intramolecular disulfide bonds. Two natural candidates for bridge formation Cys2 Cys8 that, located on flexible N-terminal domain, can easily come contact. A third potentially important residue is Cys122 that close model VDAC3. Here we analyzed impact SS bonds through molecular dynamics simulations derivatives (dubbed SS-2-8, SS-2-122, SS-8-122) including a single bond. Simulations showed SS-8-122, fragment 1-7 crosses top part barrel partially occluding pore causing 20% drop conductance. In order identify other potential channel-occluding bonds, used set neural networks bioinformatics algorithms, after filtering with steric constraints imposed 3D-structure. We identified species, namely SS-8-65, SS-2-36 SS-8-36. While conductance SS-8-65 about 30% lower than species without SS-8-36 was 40-50% lower. results show how VDAC3 able modulate its size current exploiting mobility forming, upon external stimuli, bridges cysteine residues space.