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Decrypting Strong and Weak Single-Walled Carbon Nanotubes Interactions with Mitochondrial Voltage-Dependent Anion
Michael González-Durruthy1, Adriano V Werhli2, Vinicius Seus2
1Institute of Biological Sciences (ICB)- Federal University of Rio Grande - FURG, Postgraduate Program in Physiological Sciences, Cx. P. 474, CEP 96200-970, Rio Grande, RS, Brazil. gonzalezdurruthy.furg@gmail.com.
Abstract:
The current molecular docking study provided the Free Energy of Binding (FEB) for the interaction (nanotoxicity) between VDAC mitochondrial channels of three species (VDAC1-Mus musculus, VDAC1-Homo sapiens, VDAC2-Danio rerio) with SWCNT-H, SWCNT-OH, SWCNT-COOH carbon nanotubes. The general results showed that the FEB values were statistically more negative (p < 0.05) in the following order: (SWCNT-VDAC2-Danio rerio) > (SWCNT-VDAC1-Mus musculus) > (SWCNT-VDAC1-Homo sapiens) > (ATP-VDAC). More negative FEB values for SWCNT-COOH and OH were found in VDAC2-Danio rerio when compared with VDAC1-Mus musculus and VDAC1-Homo sapiens (p < 0.05). In addition, a significant correlation (0.66 > r2 > 0.97) was observed between n-Hamada index and VDAC nanotoxicity (or FEB) for the zigzag topologies of SWCNT-COOH and SWCNT-OH. Predictive Nanoparticles-Quantitative-Structure Binding-Relationship models (nano-QSBR) for strong and weak SWCNT-VDAC docking interactions were performed using Perturbation Theory, regression and classification models. Thus, 405 SWCNT-VDAC interactions were predicted using a nano-PT-QSBR classifications model with high accuracy, specificity, and sensitivity (73-98%) in training and validation series, and a maximum AUROC value of 0.978. In addition, the best regression model was obtained with Random Forest (R2 of 0.833, RMSE of 0.0844), suggesting an excellent potential to predict SWCNT-VDAC channel nanotoxicity. All study data are available at https://doi.org/10.6084/m9.figshare.4802320.v2 .
Insights
This study used molecular docking to assess nanotoxicity, finding that carbon nanotubes bind more strongly to zebrafish VDAC2 channels than to human or mouse VDAC1 channels. Predictive models accurately forecast these interactions, aiding nanotoxicology research.
Area of Science:
- Nanotoxicology
- Computational Chemistry
- Mitochondrial Biology
Background:
- Voltage-dependent anion channels (VDACs) are crucial mitochondrial porins involved in cellular energy metabolism and apoptosis.
- Carbon nanotubes (CNTs) are widely used nanomaterials with potential for cellular interactions and toxicity.
- Understanding CNT-VDAC interactions is vital for assessing nanomaterial safety and biological impact.
Purpose of the Study:
- To computationally investigate the binding energy (Free Energy of Binding - FEB) between different functionalized CNTs and VDAC channels from three species.
- To establish quantitative structure-activity relationships (QSAR) for predicting CNT-VDAC interactions and nanotoxicity.
- To develop predictive models for CNT-VDAC docking interactions.
Main Methods:
- Molecular docking simulations were performed to calculate the FEB for interactions between SWCNTs (SWCNT-H, SWCNT-OH, SWCNT-COOH) and VDAC channels (VDAC1-Mus musculus, VDAC1-Homo sapiens, VDAC2-Danio rerio).
- Nanoparticles-Quantitative-Structure Binding-Relationship (nano-QSBR) models were developed using Perturbation Theory, regression, and classification techniques.
- Correlation analysis was used to assess the relationship between the n-Hamada index and VDAC nanotoxicity.
Main Results:
- Zebrafish VDAC2 exhibited significantly more negative FEB values with SWCNTs compared to human and mouse VDAC1 channels (p < 0.05).
- SWCNT-COOH and SWCNT-OH showed stronger binding to VDAC2-Danio rerio than to VDAC1 orthologs.
- A strong correlation (0.66 < r² < 0.97) was found between the n-Hamada index and VDAC nanotoxicity for zigzag CNT topologies.
- Predictive nano-QSBR models achieved high accuracy (73-98%) and an AUROC of 0.978 for classifying SWCNT-VDAC interactions.
- A Random Forest regression model demonstrated excellent predictive potential (R² = 0.833, RMSE = 0.0844).
Conclusions:
- Species-specific differences exist in VDAC channel susceptibility to CNT-induced nanotoxicity.
- Functionalized CNTs, particularly SWCNT-COOH and SWCNT-OH, show a higher binding affinity for zebrafish VDAC2.
- Developed nano-QSBR models provide a robust framework for predicting CNT-VDAC interactions and assessing potential nanotoxicity.
- This study offers valuable insights into the molecular mechanisms of CNTs interacting with mitochondrial VDAC channels.