title: DNA intercalation optimized by two-step molecular lock mechanism.
abstract: The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators.
authors.affiliation: Department of Physics, Northeastern University, Boston, MA, 02115, USA.|Physics Department, King Abdulaziz University, Rabigh, 21911, Saudi Arabia.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Almaqwashi
authors.affiliation: Department of Chemistry-BMC, Uppsala University, Uppsala, SE-75123, Sweden.|Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, SE-41296, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, SE-41296, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Lincoln
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Ioulia
authors.initials: I
authors.lastname: Rouzina
authors.affiliation: Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, SE-41296, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Westerlund
authors.affiliation: Department of Physics, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Williams
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D000072760:Single Molecule Imaging
chemical_list: D007364:Intercalating Agents; D004247:DNA