Computational modeling on mitochondrial channel nanotoxicity

Abstract

Herein, we evaluated the interactions between the zig-zag-single-walled carbon nanotube (z-z-SWCNT(8.0)) and the ATP-entry-point of the human mitochondrial voltage-dependent anion-selective chan-nel (hVDAC1). For this purpose, both molecular docking and molecular dynamics simulations wereperformed. The flexibility properties of the referred ATP-entry-point was efficiently modeled usingcrystallographic validation-based on Ramachandran plot. The preferred conformations obtained for thissegment were able to establish very favorable interactions with the ligands (ATP and z-z-SWCNT). Next,using both molecular docking and molecular dynamics simulations, we demonstrated that z-z-SWCNTcan directly prevent the ATP-transition from its first entry-point residue (MET1). We suggested that theassociated z-z-SWCNT aggregation can be responsible by avoiding the natural biochemical steps for theATP-transport, according to a nanotoxicity mechanism based on hydrophobic interactions. The dockingfree energy of z-z-SWCNT/hVDAC1 and ATP/hVDAC1 complexes was remarkably close, according to localperturbation maps of the catalytic residues’ cluster (i.e. MET1, ARG2, GLY3, SER4, ALA5). On the other hand,the results of molecular dynamics simulations match the ones of the docking simulations, reinforcing thehVDAC1 channel nanotoxicity hypothesis. Overall, the obtained results could open new opportunitiestowards the rational design of new carbon nanomaterials and in silico mitotarget drug-discovery.