title: 2D-IR Spectroscopy Shows that Optimized DNA Minor Groove Binding of Hoechst33258 Follows an Induced Fit Model.
abstract: The induced fit binding model describes a conformational change occurring when a small molecule binds to its biomacromolecular target. The result is enhanced noncovalent interactions between the ligand and biomolecule. Induced fit is well-established for small molecule-protein interactions, but its relevance to small molecule-DNA binding is less clear. We investigate the molecular determinants of Hoechst33258 binding to its preferred A-tract sequence relative to a suboptimal alternating A-T sequence. Results from two-dimensional infrared spectroscopy, which is sensitive to H-bonding and molecular structure changes, show that Hoechst33258 binding results in loss of the minor groove spine of hydration in both sequences, but an additional perturbation of the base propeller twists occurs in the A-tract binding region. This induced fit maximizes favorable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the molecular details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding molecules.
authors.affiliation: Department of Physics, University of Strathclyde, SUPA , 107 Rottenrow East, Glasgow G4 0NG, United Kingdon.
authors.forename: Lennart A I
authors.initials: LA
authors.lastname: Ramakers
authors.affiliation: Department of Physics, University of Strathclyde, SUPA , 107 Rottenrow East, Glasgow G4 0NG, United Kingdon.
authors.forename: Gordon
authors.initials: G
authors.lastname: Hithell
authors.affiliation: Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: May
authors.affiliation: Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory , Harwell, Oxford OX11 0QX, United Kingdom.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Greetham
authors.affiliation: Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory , Harwell, Oxford OX11 0QX, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Donaldson
authors.affiliation: Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory , Harwell, Oxford OX11 0QX, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Towrie
authors.affiliation: Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory , Harwell, Oxford OX11 0QX, United Kingdom.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Parker
authors.affiliation: Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
authors.forename: Glenn A
authors.identifier: 0000-0002-4896-113X
authors.initials: GA
authors.lastname: Burley
authors.affiliation: Department of Physics, University of Strathclyde, SUPA , 107 Rottenrow East, Glasgow G4 0NG, United Kingdon.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Hunt
mesh_terms: D001665:Binding Sites; D006690:Bisbenzimidazole / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared
chemical_list: D008024:Ligands; D004247:DNA; D006690:Bisbenzimidazole