Modeling and Analysis of Intercalant Effects on Circular DNA Conformation

Eric Krueger, Jiwook Shim, Arman Fathizadeh, Angela Nicole Chang, Basheer Subei, Katie M. Yocham, Paul H. Davis, Elton Graugnard, Fatemeh Khalili-Araghi, Rashid Bashir, David Estrada, Daniel Fologea

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The large-scale conformation of DNA molecules plays a critical role in many basic elements of cellular functionality and viability. By targeting the structural properties of DNA, many cancer drugs, such as anthracyclines, effectively inhibit tumor growth but can also produce dangerous side effects. To enhance the development of innovative medications, rapid screening of structural changes to DNA can provide important insight into their mechanism of interaction. In this study, we report changes to circular DNA conformation from intercalation with ethidium bromide using all-atom molecular dynamics simulations and characterized experimentally by translocation through a silicon nitride solid-state nanopore. Our measurements reveal three distinct current blockade levels and a 6-fold increase in translocation times for ethidium bromide-treated circular DNA as compared to untreated circular DNA. We attribute these increases to changes in the supercoiled configuration hypothesized to be branched or looped structures formed in the circular DNA molecule. Further evidence of the conformational changes is demonstrated by qualitative atomic force microscopy analysis. These results expand the current methodology for predicting and characterizing DNA tertiary structure and advance nanopore technology as a platform for deciphering structural changes of other important biomolecules.

Original languageEnglish (US)
Pages (from-to)8910-8917
Number of pages8
JournalACS Nano
Volume10
Issue number9
DOIs
StatePublished - Sep 27 2016

Fingerprint

Circular DNA
Conformations
DNA
deoxyribonucleic acid
Nanopores
Ethidium
Molecules
Anthracyclines
Biomolecules
Intercalation
Molecular dynamics
Structural properties
bromides
Tumors
Atomic force microscopy
Screening
Atoms
Computer simulation
Silicon nitride
viability

All Science Journal Classification (ASJC) codes

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Cite this

Krueger, E., Shim, J., Fathizadeh, A., Chang, A. N., Subei, B., Yocham, K. M., ... Fologea, D. (2016). Modeling and Analysis of Intercalant Effects on Circular DNA Conformation. ACS Nano, 10(9), 8910-8917. https://doi.org/10.1021/acsnano.6b04876
Krueger, Eric ; Shim, Jiwook ; Fathizadeh, Arman ; Chang, Angela Nicole ; Subei, Basheer ; Yocham, Katie M. ; Davis, Paul H. ; Graugnard, Elton ; Khalili-Araghi, Fatemeh ; Bashir, Rashid ; Estrada, David ; Fologea, Daniel. / Modeling and Analysis of Intercalant Effects on Circular DNA Conformation. In: ACS Nano. 2016 ; Vol. 10, No. 9. pp. 8910-8917.
@article{137f76e4b65d46128ef23d22086685bb,
title = "Modeling and Analysis of Intercalant Effects on Circular DNA Conformation",
abstract = "The large-scale conformation of DNA molecules plays a critical role in many basic elements of cellular functionality and viability. By targeting the structural properties of DNA, many cancer drugs, such as anthracyclines, effectively inhibit tumor growth but can also produce dangerous side effects. To enhance the development of innovative medications, rapid screening of structural changes to DNA can provide important insight into their mechanism of interaction. In this study, we report changes to circular DNA conformation from intercalation with ethidium bromide using all-atom molecular dynamics simulations and characterized experimentally by translocation through a silicon nitride solid-state nanopore. Our measurements reveal three distinct current blockade levels and a 6-fold increase in translocation times for ethidium bromide-treated circular DNA as compared to untreated circular DNA. We attribute these increases to changes in the supercoiled configuration hypothesized to be branched or looped structures formed in the circular DNA molecule. Further evidence of the conformational changes is demonstrated by qualitative atomic force microscopy analysis. These results expand the current methodology for predicting and characterizing DNA tertiary structure and advance nanopore technology as a platform for deciphering structural changes of other important biomolecules.",
author = "Eric Krueger and Jiwook Shim and Arman Fathizadeh and Chang, {Angela Nicole} and Basheer Subei and Yocham, {Katie M.} and Davis, {Paul H.} and Elton Graugnard and Fatemeh Khalili-Araghi and Rashid Bashir and David Estrada and Daniel Fologea",
year = "2016",
month = "9",
day = "27",
doi = "10.1021/acsnano.6b04876",
language = "English (US)",
volume = "10",
pages = "8910--8917",
journal = "ACS Nano",
issn = "1936-0851",
publisher = "American Chemical Society",
number = "9",

}

Krueger, E, Shim, J, Fathizadeh, A, Chang, AN, Subei, B, Yocham, KM, Davis, PH, Graugnard, E, Khalili-Araghi, F, Bashir, R, Estrada, D & Fologea, D 2016, 'Modeling and Analysis of Intercalant Effects on Circular DNA Conformation', ACS Nano, vol. 10, no. 9, pp. 8910-8917. https://doi.org/10.1021/acsnano.6b04876

Modeling and Analysis of Intercalant Effects on Circular DNA Conformation. / Krueger, Eric; Shim, Jiwook; Fathizadeh, Arman; Chang, Angela Nicole; Subei, Basheer; Yocham, Katie M.; Davis, Paul H.; Graugnard, Elton; Khalili-Araghi, Fatemeh; Bashir, Rashid; Estrada, David; Fologea, Daniel.

In: ACS Nano, Vol. 10, No. 9, 27.09.2016, p. 8910-8917.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Modeling and Analysis of Intercalant Effects on Circular DNA Conformation

AU - Krueger, Eric

AU - Shim, Jiwook

AU - Fathizadeh, Arman

AU - Chang, Angela Nicole

AU - Subei, Basheer

AU - Yocham, Katie M.

AU - Davis, Paul H.

AU - Graugnard, Elton

AU - Khalili-Araghi, Fatemeh

AU - Bashir, Rashid

AU - Estrada, David

AU - Fologea, Daniel

PY - 2016/9/27

Y1 - 2016/9/27

N2 - The large-scale conformation of DNA molecules plays a critical role in many basic elements of cellular functionality and viability. By targeting the structural properties of DNA, many cancer drugs, such as anthracyclines, effectively inhibit tumor growth but can also produce dangerous side effects. To enhance the development of innovative medications, rapid screening of structural changes to DNA can provide important insight into their mechanism of interaction. In this study, we report changes to circular DNA conformation from intercalation with ethidium bromide using all-atom molecular dynamics simulations and characterized experimentally by translocation through a silicon nitride solid-state nanopore. Our measurements reveal three distinct current blockade levels and a 6-fold increase in translocation times for ethidium bromide-treated circular DNA as compared to untreated circular DNA. We attribute these increases to changes in the supercoiled configuration hypothesized to be branched or looped structures formed in the circular DNA molecule. Further evidence of the conformational changes is demonstrated by qualitative atomic force microscopy analysis. These results expand the current methodology for predicting and characterizing DNA tertiary structure and advance nanopore technology as a platform for deciphering structural changes of other important biomolecules.

AB - The large-scale conformation of DNA molecules plays a critical role in many basic elements of cellular functionality and viability. By targeting the structural properties of DNA, many cancer drugs, such as anthracyclines, effectively inhibit tumor growth but can also produce dangerous side effects. To enhance the development of innovative medications, rapid screening of structural changes to DNA can provide important insight into their mechanism of interaction. In this study, we report changes to circular DNA conformation from intercalation with ethidium bromide using all-atom molecular dynamics simulations and characterized experimentally by translocation through a silicon nitride solid-state nanopore. Our measurements reveal three distinct current blockade levels and a 6-fold increase in translocation times for ethidium bromide-treated circular DNA as compared to untreated circular DNA. We attribute these increases to changes in the supercoiled configuration hypothesized to be branched or looped structures formed in the circular DNA molecule. Further evidence of the conformational changes is demonstrated by qualitative atomic force microscopy analysis. These results expand the current methodology for predicting and characterizing DNA tertiary structure and advance nanopore technology as a platform for deciphering structural changes of other important biomolecules.

UR - http://www.scopus.com/inward/record.url?scp=84989181283&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84989181283&partnerID=8YFLogxK

U2 - 10.1021/acsnano.6b04876

DO - 10.1021/acsnano.6b04876

M3 - Article

C2 - 27559753

AN - SCOPUS:84989181283

VL - 10

SP - 8910

EP - 8917

JO - ACS Nano

JF - ACS Nano

SN - 1936-0851

IS - 9

ER -

Krueger E, Shim J, Fathizadeh A, Chang AN, Subei B, Yocham KM et al. Modeling and Analysis of Intercalant Effects on Circular DNA Conformation. ACS Nano. 2016 Sep 27;10(9):8910-8917. https://doi.org/10.1021/acsnano.6b04876