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.
authors: Eric
authors: E
authors: Krueger
authors: Biomedical Engineering Department, Rowan University , Glassboro, New Jersey 08028, United States.
authors: Jiwook
authors: J
authors: Shim
authors: Department of Physics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors: Arman
authors: A
authors: Fathizadeh
authors: Angela Nicole
authors: AN
authors: Chang
authors: Department of Physics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors: Basheer
authors: B
authors: Subei
authors: Katie M
authors: KM
authors: Yocham
authors: Paul H
authors: PH
authors: Davis
authors: Elton
authors: E
authors: Graugnard
authors: Department of Physics, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors: Fatemeh
authors: F
authors: Khalili-Araghi
authors: Rashid
authors: R
authors: Bashir
authors: David
authors: D
authors: Estrada
authors: Daniel
authors: D
authors: Fologea
mesh_terms: D004247:DNA / Q000737:chemistry; D004270:DNA, Circular; D004996:Ethidium / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D009690:Nucleic Acid Conformation
chemical_list: D004270:DNA, Circular; D004247:DNA; D004996:Ethidium
keywords: DNA conformation; DNA translocation; ethidium bromide; intercalation; molecular dynamics; nanopore