title: Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA.
abstract: The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities. Given the ubiquitous participation of the histidine-based imidazole group in protein recognition and catalysis events, single histidine-like modified duplexes were investigated. Tethering histamine to the C5 of the thymine base via an amide bond, allows the flexible positioning of the imidazole function in the major groove. The mutual interactions between the imidazole and the duplex and its influence on the imidazolium pKaH are investigated by placing a single modified thymine at four different positions in the center of the 14mer double helix. Using NMR and unrestrained molecular dynamics, a structural motif involving the formation of a hydrogen bond between the imidazole and the Hoogsteen side of the guanine bases of two neighboring GC base pairs is established. The motif contributes to a stabilization against thermal melting of 6°C and is key in modulating the pKaH of the imidazolium group. The general features, prerequisites and generic character of the new pKaH-regulating motif are described.
authors.affiliation: Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Buyst
authors.affiliation: Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
authors.forename: Vicky
authors.initials: V
authors.lastname: Gheerardijn
authors.affiliation: Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Fehér
authors.affiliation: Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Van Gasse
authors.affiliation: Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: Van Den Begin
authors.affiliation: Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium Jose.Martins@UGent.be.
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
authors.affiliation: Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Gent, Oost-Vlaanderen 9000, Belgium Annemieke.Madder@UGent.be.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Madder
mesh_terms: D020137:Base Pair Mismatch; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D059372:Nucleotide Motifs; D013941:Thymine / Q000737:chemistry
chemical_list: D007093:Imidazoles; C029899:imidazole; D004247:DNA; D013941:Thymine