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High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
Published on: February 7, 2019
Study on the binding interaction between perfluoroalkyl acids and DNA
1AQSIQ Key Laboratory of Drug Detection, Fujian International Travel Healthcare Center, Fujian Entry-Exit Inspection and Quarantine Bureau of P.R.C., Fujian, 350001, China.
Abstract:
Perfluoroalkyl acids (PFAAs) are carcinogens, and elucidating their DNA binding properties is crucial for understanding PFAA genotoxicity. We have investigated the binding mode and affinity of five PFAAs to seven DNA molecules using fluorescence displacement and molecular docking analysis. DNA conformational changes upon PFAA binding were also examined by circular dichroism (CD). The data revealed that DNA intercalation was the dominant interaction mode of the PFAAs; however, these molecules also bound to grooves. The dissociation constants for the PFAAs ranged between 0.11 and 1,217.14 μM, and between 3.46 and 2,141.21 μM for DNA intercalation and groove binding, respectively. PFAAs that contain longer carbon chains had stronger DNA intercalation affinities. Binding to DNA was stronger for perfluoroalkyl sulfonates than for perfluorcarboxyl acids that contain the same number of carbons. This observation is postulated to arise from the presence of more fluorine and oxygen atoms in perfluoroalkyl sulfonates acting as hydrogen bond donors that facilitate stronger DNA intercalation. The binding of the PFAAs to DNA showed some CT-DNA sequence selectivity. Molecular docking analysis confirmed the DNA binding mode and affinities of the PFAAs. CD analysis revealed that the PFAAs weakened DNA base stacking and loosened DNA helicity. The present study has improved our understanding of the formation of PFAA-DNA adducts.
Insights
Perfluoroalkyl acids (PFAAs) bind to DNA primarily through intercalation, with longer chains and sulfonate structures showing stronger affinity. This interaction can alter DNA structure, impacting genotoxicity.
Area of Science:
- Environmental Chemistry
- Molecular Toxicology
- Biochemistry
Background:
- Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants with known carcinogenic properties.
- Understanding the genotoxicity of PFAAs requires detailed knowledge of their interaction with DNA.
- Elucidating the molecular mechanisms of PFAA-DNA binding is crucial for risk assessment.
Purpose of the Study:
- To investigate the DNA binding modes and affinities of five PFAAs.
- To determine the influence of PFAA structure on DNA binding.
- To examine PFAA-induced DNA conformational changes.
Main Methods:
- Fluorescence displacement assays to measure binding affinity.
- Molecular docking simulations to predict binding modes.
- Circular dichroism (CD) spectroscopy to assess DNA conformational changes.
Main Results:
- PFAAs predominantly bind to DNA via intercalation, with some groove binding observed.
- Dissociation constants varied, with longer carbon chains and perfluoroalkyl sulfonates exhibiting stronger intercalation affinities.
- CD analysis indicated PFAAs weaken DNA base stacking and helicity, suggesting PFAA-DNA adduct formation.
Conclusions:
- PFAA binding to DNA is sequence-selective and influenced by molecular structure.
- The study provides insights into PFAA-DNA adduct formation and genotoxicity mechanisms.
- Findings contribute to a better understanding of the environmental health risks associated with PFAAs.
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