title: An Organometallic Compound which Exhibits a DNA Topology-Dependent One-Stranded Intercalation Mode.
abstract: Understanding how small molecules interact with DNA is essential since it underlies a multitude of pathological conditions and therapeutic interventions. Many different intercalator compounds have been studied because of their activity as mutagens or drugs, but little is known regarding their interaction with nucleosomes, the protein-packaged form of DNA in cells. Here, using crystallographic methods and molecular dynamics simulations, we discovered that adducts formed by [(η(6) -THA)Ru(ethylenediamine)Cl][PF6 ] (THA=5,8,9,10-tetrahydroanthracene; RAED-THA-Cl[PF6 ]) in the nucleosome comprise a novel one-stranded intercalation and DNA distortion mode. Conversely, the THA group in fact remains solvent exposed and does not disrupt base stacking in RAED-THA adducts on B-form DNA. This newly observed DNA binding mode and topology dependence may actually be prevalent and should be considered when studying covalently binding intercalating compounds.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Giulia
authors.identifier: 0000-0003-1404-8737
authors.initials: G
authors.lastname: Palermo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
authors.forename: Zenita
authors.initials: Z
authors.lastname: Adhireksan
authors.affiliation: Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Murray
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Thibaud
authors.initials: T
authors.lastname: von Erlach
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland. ursula.roethlisberger@epfl.ch.
authors.forename: Ursula
authors.identifier: 0000-0002-1704-8591
authors.initials: U
authors.lastname: Rothlisberger
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore. davey@ntu.edu.sg.
authors.forename: Curt A
authors.identifier: 0000-0003-2632-775X
authors.initials: CA
authors.lastname: Davey
mesh_terms: D000873:Anthracenes / Q000737:chemistry*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005029:Ethylenediamines / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009942:Organometallic Compounds / Q000737:chemistry*
chemical_list: D000873:Anthracenes; D005029:Ethylenediamines; D007364:Intercalating Agents; D009942:Organometallic Compounds; C031234:ethylenediamine; D004247:DNA
keywords: DNA adducts; anticancer agent; intercalators; molecular dynamics; organometallics