title: Double-coding nucleic acids: introduction of a nucleobase sequence in the major groove of the DNA duplex using double-headed nucleotides.
abstract: A series of double-headed nucleosides were synthesized using the Sonogashira cross-coupling reaction. In the reactions, additional nucleobases (thymine, cytosine, adenine, or guanine) were attached to the 5-position of 2'-deoxyuridine or 2'-deoxycytidine through a propyne linker. The modified nucleosides were incorporated into oligonucleotides, and these were combined in different duplexes that were analyzed by thermal denaturation studies. All of the monomers were well tolerated in the DNA duplexes and induced only small changes in the thermal stability. Consecutive incorporations of the monomers led to increases in duplex stability owing to increased stacking interactions. The modified nucleotide monomers maintained the Watson-Crick base pair fidelity. Stable duplexes were observed with heavily modified oligonucleotides featuring 14 consecutive incorporations of different double-headed nucleotide monomers. Thus, modified duplexes with an array of nucleobases on the exterior of the duplex were designed. Molecular dynamics simulations demonstrated that the additional nucleobases could expose their Watson-Crick and/or Hoogsteen faces for recognition in the major groove. This presentation of nucleobases may find applications in providing molecular information without unwinding the duplex.
authors.affiliation: Department of Physics, Chemistry and Pharmacy and ‡Department of Biochemistry and Molecular Biology, Nucleic Acid Center, University of Southern Denmark , 5230 Odense M, Denmark.
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Antoni Figueras
authors.initials: AF
authors.lastname: Sorinas
authors.forename: Lise J
authors.initials: LJ
authors.lastname: Nielsen
authors.forename: Maria
authors.initials: M
authors.lastname: Slot
authors.forename: Kirstine
authors.initials: K
authors.lastname: Skytte
authors.forename: Annie S
authors.initials: AS
authors.lastname: Nielsen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jensen
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Sharma
authors.forename: Birte
authors.initials: B
authors.lastname: Vester
authors.forename: Michael
authors.initials: M
authors.lastname: Petersen
authors.forename: Poul
authors.initials: P
authors.lastname: Nielsen
mesh_terms: D020029:Base Pairing; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D003856:Deoxyuracil Nucleotides / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009696:Nucleic Acids / Q000737:chemistry*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D003856:Deoxyuracil Nucleotides; D009696:Nucleic Acids; D009705:Nucleosides; D009711:Nucleotides; D004247:DNA; C007267:2'-deoxyuridylic acid