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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.


(a) Schematic for the capture of DNA molecules into the nanopore. The dash line illustrates the absorbing boundary within which the driving force prevails over the diffusion effect. The arrows illustrate the motion of DNA molecules. The entropy barrier is near the pore opening by a distance of Rg. (b) The distribution of electric potential (U), entropic cost (−TΔS), and electrochemical potential (μe) as a function of distance r from the pore center. The dash lines indicate the position of entropy barrier and absorbing boundary.
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f1: (a) Schematic for the capture of DNA molecules into the nanopore. The dash line illustrates the absorbing boundary within which the driving force prevails over the diffusion effect. The arrows illustrate the motion of DNA molecules. The entropy barrier is near the pore opening by a distance of Rg. (b) The distribution of electric potential (U), entropic cost (−TΔS), and electrochemical potential (μe) as a function of distance r from the pore center. The dash lines indicate the position of entropy barrier and absorbing boundary.

Mentions: As described by Wanunu et al.28, the transport path of DNA through a nanopore can be divided into five steps: (i) free diffusion to a semi-spherical absorbing boundary, (ii) biased diffusion to the nanopore, (iii) DNA threading into the nanopore, (iv) DNA translocation through the nanopore, and (v) DNA escaping away from the nanopore. The translocation throughput is determined by the absorbing boundary and the threading entropic barrier. Figure 1(a) illustrates both critical factors in capturing a DNA molecule into a nanopore. The entropy barrier is located near the pore opening by a distance on the order of Rg, the gyration radius of the DNA molecule. The distribution of electric potential, entropic cost, and electrochemical potential as a function of distance from the pore opening are shown in Fig. 1(b). Quantitatively, the number of translocation events per unit time, or the capture rate J, can be described by Kramers’ theory aswhere q is the effect charge of DNA end segment, ΔV is the applied voltage across the electrodes, U is the entropic barrier energy, kB is Boltzmann constant, and T is the absolute temperature. The collision frequency ω is proportional to the throughput from the absorbing boundary and can be written as πcμd2ΔV/4h28, where c is DNA concentration, μ is electrophoretic mobility, d and h are diameter and thickness of the nanopore. The electrophoretic mobility μ is proportional to , where ρ and l are linear charge density and persistence length of DNA molecules. Due to steric hindrance effect, the success rate of threading a DNA end segment into the pore is better described as proportional to (d−2r)2, instead of d2, where r is the effective radius of the DNA molecule. Combining the pre-exponential invariant as a constant A, the total capture rate J is derived as follows:


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)

(a) Schematic for the capture of DNA molecules into the nanopore. The dash line illustrates the absorbing boundary within which the driving force prevails over the diffusion effect. The arrows illustrate the motion of DNA molecules. The entropy barrier is near the pore opening by a distance of Rg. (b) The distribution of electric potential (U), entropic cost (−TΔS), and electrochemical potential (μe) as a function of distance r from the pore center. The dash lines indicate the position of entropy barrier and absorbing boundary.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: (a) Schematic for the capture of DNA molecules into the nanopore. The dash line illustrates the absorbing boundary within which the driving force prevails over the diffusion effect. The arrows illustrate the motion of DNA molecules. The entropy barrier is near the pore opening by a distance of Rg. (b) The distribution of electric potential (U), entropic cost (−TΔS), and electrochemical potential (μe) as a function of distance r from the pore center. The dash lines indicate the position of entropy barrier and absorbing boundary.
Mentions: As described by Wanunu et al.28, the transport path of DNA through a nanopore can be divided into five steps: (i) free diffusion to a semi-spherical absorbing boundary, (ii) biased diffusion to the nanopore, (iii) DNA threading into the nanopore, (iv) DNA translocation through the nanopore, and (v) DNA escaping away from the nanopore. The translocation throughput is determined by the absorbing boundary and the threading entropic barrier. Figure 1(a) illustrates both critical factors in capturing a DNA molecule into a nanopore. The entropy barrier is located near the pore opening by a distance on the order of Rg, the gyration radius of the DNA molecule. The distribution of electric potential, entropic cost, and electrochemical potential as a function of distance from the pore opening are shown in Fig. 1(b). Quantitatively, the number of translocation events per unit time, or the capture rate J, can be described by Kramers’ theory aswhere q is the effect charge of DNA end segment, ΔV is the applied voltage across the electrodes, U is the entropic barrier energy, kB is Boltzmann constant, and T is the absolute temperature. The collision frequency ω is proportional to the throughput from the absorbing boundary and can be written as πcμd2ΔV/4h28, where c is DNA concentration, μ is electrophoretic mobility, d and h are diameter and thickness of the nanopore. The electrophoretic mobility μ is proportional to , where ρ and l are linear charge density and persistence length of DNA molecules. Due to steric hindrance effect, the success rate of threading a DNA end segment into the pore is better described as proportional to (d−2r)2, instead of d2, where r is the effective radius of the DNA molecule. Combining the pre-exponential invariant as a constant A, the total capture rate J is derived as follows:

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.