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Revealing Three Stages of DNA-Cisplatin Reaction by a Solid-State Nanopore.

Zhou Z, Hu Y, Shan X, Li W, Bai X, Wang P, Lu X - Sci Rep (2015)

Bottom Line: The interaction processes are found to be well elucidated by the evolution of the capture rate of DNA-cisplatin complex, which is defined as the number of their translocation events through the nanopore in unit time.In the second stage, by forming di-adducts, the capture rate increases as DNA molecules are softened, appears as the reduced persistence length of the DNA-cisplatin adducts.In the third stage, the capture rate decreases again as a result of DNA aggregation.

View Article: PubMed Central - PubMed

Affiliation: Beijing National Laboratory for Condensed-Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing 100190, People's Republic of China.

ABSTRACT
The dynamic structural behavior in DNA due to interaction with cisplatin is essential for the functionality of platinum-based anti-cancer drugs. Here we report a novel method to monitor the interaction progress in DNA-cisplatin reaction in real time with a solid-state nanopore. The interaction processes are found to be well elucidated by the evolution of the capture rate of DNA-cisplatin complex, which is defined as the number of their translocation events through the nanopore in unit time. In the first stage, the capture rate decreases rapidly due to DNA discharging as the positive-charged hydrated cisplatin molecules initially bond to the negative-charged DNA and form mono-adducts. In the second stage, by forming di-adducts, the capture rate increases as DNA molecules are softened, appears as the reduced persistence length of the DNA-cisplatin adducts. In the third stage, the capture rate decreases again as a result of DNA aggregation. Our study demonstrates a new single-molecule tool in exploring dynamic behaviors during drug-DNA reactions and may have future application in fast drug screening.

No MeSH data available.


Stage III.(a) Capture rate J versus reaction time. Inset: schematic of DNA micro-loop and crosslink formed by di-adduct. ΔV = 200 mV, d = 5.3 nm. (b) Effect radius r versus reaction time. (c) Aggregation time τB versus nanopore diameter with concentration α = 10, ΔV = 500 mV. The solid lines in (b) and (c) are linear fits. (d) The correlation between rate constant k3 and concentration ratio α. Solid line is a linear fit with slope equals 1.9 ± 0.1.
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f5: Stage III.(a) Capture rate J versus reaction time. Inset: schematic of DNA micro-loop and crosslink formed by di-adduct. ΔV = 200 mV, d = 5.3 nm. (b) Effect radius r versus reaction time. (c) Aggregation time τB versus nanopore diameter with concentration α = 10, ΔV = 500 mV. The solid lines in (b) and (c) are linear fits. (d) The correlation between rate constant k3 and concentration ratio α. Solid line is a linear fit with slope equals 1.9 ± 0.1.

Mentions: Along a DNA molecule chain, some mono-adducts have no guanine or adenine bases as their neighbors and thus cannot form di-adducts in the second stage. However, they may bond to guanine or adenine base further away along the DNA molecular chain due to thermal fluctuation. By forming di-adducts with a further-away base, the drug molecules induces micro-loop structures and crosslinks (see the schematic inset of Fig. 5a), which eventually drive the DNA molecule to condense to a compact globule15. In such processes, the effective diameter of the DNA molecule increases, and then the free energy barrier of DNA being threaded into the solid-state nanopore increases as well. The steric hindrance effect plays a dominate role in determining the capture rate in this stage,where A3 is a constant in this stage. The capture rate J decreases as the effective diameter 2r increases up to the nanopore diameter d by when DNA molecule will not translocate through the nanopore anymore. Figure 5a shows the evolution of capture rate in this stage for DNA sample mixed with 10 μM cisplatin (α = 1). The diameter of the pore is 5.3 nm and the driving voltage is 200 mV. The capture rate decreases from 22.5 minute−1 to 9 minute−1 in a period of 12 hours.


Revealing Three Stages of DNA-Cisplatin Reaction by a Solid-State Nanopore.

Zhou Z, Hu Y, Shan X, Li W, Bai X, Wang P, Lu X - Sci Rep (2015)

Stage III.(a) Capture rate J versus reaction time. Inset: schematic of DNA micro-loop and crosslink formed by di-adduct. ΔV = 200 mV, d = 5.3 nm. (b) Effect radius r versus reaction time. (c) Aggregation time τB versus nanopore diameter with concentration α = 10, ΔV = 500 mV. The solid lines in (b) and (c) are linear fits. (d) The correlation between rate constant k3 and concentration ratio α. Solid line is a linear fit with slope equals 1.9 ± 0.1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493569&req=5

f5: Stage III.(a) Capture rate J versus reaction time. Inset: schematic of DNA micro-loop and crosslink formed by di-adduct. ΔV = 200 mV, d = 5.3 nm. (b) Effect radius r versus reaction time. (c) Aggregation time τB versus nanopore diameter with concentration α = 10, ΔV = 500 mV. The solid lines in (b) and (c) are linear fits. (d) The correlation between rate constant k3 and concentration ratio α. Solid line is a linear fit with slope equals 1.9 ± 0.1.
Mentions: Along a DNA molecule chain, some mono-adducts have no guanine or adenine bases as their neighbors and thus cannot form di-adducts in the second stage. However, they may bond to guanine or adenine base further away along the DNA molecular chain due to thermal fluctuation. By forming di-adducts with a further-away base, the drug molecules induces micro-loop structures and crosslinks (see the schematic inset of Fig. 5a), which eventually drive the DNA molecule to condense to a compact globule15. In such processes, the effective diameter of the DNA molecule increases, and then the free energy barrier of DNA being threaded into the solid-state nanopore increases as well. The steric hindrance effect plays a dominate role in determining the capture rate in this stage,where A3 is a constant in this stage. The capture rate J decreases as the effective diameter 2r increases up to the nanopore diameter d by when DNA molecule will not translocate through the nanopore anymore. Figure 5a shows the evolution of capture rate in this stage for DNA sample mixed with 10 μM cisplatin (α = 1). The diameter of the pore is 5.3 nm and the driving voltage is 200 mV. The capture rate decreases from 22.5 minute−1 to 9 minute−1 in a period of 12 hours.

Bottom Line: The interaction processes are found to be well elucidated by the evolution of the capture rate of DNA-cisplatin complex, which is defined as the number of their translocation events through the nanopore in unit time.In the second stage, by forming di-adducts, the capture rate increases as DNA molecules are softened, appears as the reduced persistence length of the DNA-cisplatin adducts.In the third stage, the capture rate decreases again as a result of DNA aggregation.

View Article: PubMed Central - PubMed

Affiliation: Beijing National Laboratory for Condensed-Matter Physics and Institute of Physics, Chinese Academy of Sciences, Beijing 100190, People's Republic of China.

ABSTRACT
The dynamic structural behavior in DNA due to interaction with cisplatin is essential for the functionality of platinum-based anti-cancer drugs. Here we report a novel method to monitor the interaction progress in DNA-cisplatin reaction in real time with a solid-state nanopore. The interaction processes are found to be well elucidated by the evolution of the capture rate of DNA-cisplatin complex, which is defined as the number of their translocation events through the nanopore in unit time. In the first stage, the capture rate decreases rapidly due to DNA discharging as the positive-charged hydrated cisplatin molecules initially bond to the negative-charged DNA and form mono-adducts. In the second stage, by forming di-adducts, the capture rate increases as DNA molecules are softened, appears as the reduced persistence length of the DNA-cisplatin adducts. In the third stage, the capture rate decreases again as a result of DNA aggregation. Our study demonstrates a new single-molecule tool in exploring dynamic behaviors during drug-DNA reactions and may have future application in fast drug screening.

No MeSH data available.