title: Conformational Dynamics of Cyanocobalamin and Its Conjugates with Peptide Nucleic Acids.
abstract: Vitamin B12also called cobalamin (Cbl) is an important enzymatic cofactor taken up by mammalian and also by many bacterial cells. Peptide nucleic acid (PNA) is a synthetic DNA analogue that has the ability to bind in a complementary manner to natural nucleic acids. Provided that PNA is efficiently delivered to cells, it could act as a steric blocker of functional DNA or RNA and regulate gene expression at the level of transcription or translation. Recently, Cbl has been examined as a transporter of various molecules to cells. Also, PNA, if covalently linked with Cbl, can be delivered to bacterial cells, but it is crucial to verify that Cbl does not change the desired PNA biological properties. We have analyzed the structure and conformational dynamics of conjugates of Cbl with a PNA monomer and oligomer. We synthesized a cyanocobalamin derivative with a PNA monomer C connected via the triazole linker and determined its NMR spectra. Using microsecond-long molecular dynamics simulations, we examined the internal dynamics of cyanocobalamin-C, its conjugate with a 14-mer PNA, and free PNA. The results suggest that all compounds acquire rather compact structures but the PNA oligomer conformations vary. For the Cbl-C conjugate the cross-peaks from the ROESY spectrum corroborated with the clusters from molecular dynamics trajectories. Within PNA the dominant interaction is stacking but the stacking bases are not necessarily neighboring in the PNA sequence. More bases stack in free PNA than in PNA of the conjugate, but stacking is less stable in free PNA. PNA in the conjugate is slightly more exposed to solvent. Overall, cyanocobalamin attached to a PNA oligomer increases the flexibility of PNA in a way that could be beneficial for its hybridization with natural nucleic acid oligomers.
authors.affiliation: Centre of New Technologies, University of Warsaw , S. Banacha 2c, 02-097 Warsaw, Poland.|Department of Drug Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw , S. Banacha 1a, 02-097 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Pieńko
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences , M. Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Aleksandra J
authors.initials: AJ
authors.lastname: Wierzba
authors.affiliation: Centre of New Technologies, University of Warsaw , S. Banacha 2c, 02-097 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Wojciechowska
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences , M. Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Gryko
authors.affiliation: Centre of New Technologies, University of Warsaw , S. Banacha 2c, 02-097 Warsaw, Poland.
authors.forename: Joanna
authors.identifier: 0000-0002-1464-5323
authors.initials: J
authors.lastname: Trylska
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D020135:Peptide Nucleic Acids / Q000737:chemistry*; D014805:Vitamin B 12 / Q000737:chemistry*
chemical_list: D020135:Peptide Nucleic Acids; D014805:Vitamin B 12