Computational modeling on mitochondrial channel nanotoxicity

• Published in: Nano today 2020-10, Vol.34, p.100913, Article 100913
• Main Authors: González-Durruthy, Michael, Giri, Amal Kanta, Moreira, Irina, Concu, Riccardo, Melo, André, Ruso, Juan M., Cordeiro, M. Natália D.S.
• Format: Article
• Language: English
• Subjects: Computational nanotoxicology; Mitotarget drug-discovery; Molecular docking; Molecular dynamic; VDAC channel
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2020.100913

[Display omitted] •Mitochondrial channel nanotoxicity induced by single walled carbon nanotubes (SWCNT).•Computational approaches based on molecular docking, ENM models, and molecular dynamic simulations in nanotoxicology.•Interactions of SWCNT with the ATP-entry-point of the human voltaje-dependent anion channel.•Rational drug-design on computational mitotarget discovery and Mitochondrial Nanomedicine. 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 channel (hVDAC1). For this purpose, both molecular docking and molecular dynamics simulations were performed. The flexibility properties of the referred ATP-entry-point was efficiently modeled using crystallographic validation-based on Ramachandran plot. The preferred conformations obtained for this segment 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-SWCNT can directly prevent the ATP-transition from its first entry-point residue (MET1). We suggested that the associated z-z-SWCNT aggregation can be responsible by avoiding the natural biochemical steps for the ATP-transport, according to a nanotoxicity mechanism based on hydrophobic interactions. The docking free energy of z-z-SWCNT/hVDAC1 and ATP/hVDAC1 complexes was remarkably close, according to local perturbation 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 the hVDAC1 channel nanotoxicity hypothesis. Overall, the obtained results could open new opportunities towards the rational design of new carbon nanomaterials and in silico mitotarget drug-discovery.