title: Tuning the activity of Zn(II) complexes in DNA cleavage: clues for design of new efficient metallo-hydrolases.
abstract: The hydrolytic ability toward plasmid DNA of a mononuclear and a binuclear Zn(II) complex with two macrocyclic ligands, containing respectively a phenanthroline (L1) and a dipyridine moiety (L2), was analyzed at different pH values and compared with their activity in bis( p-nitrophenyl)phosphate (BNPP) cleavage. Only the most nucleophilic species [ZnL1(OH)]+ and [Zn2L2(OH)2]2+, present in solution at alkaline pH values, are active in BNPP cleavage, and the dinuclear L2 complex is remarkably more active than the mononuclear L1 one. Circular dichroism and unwinding experiments show that both complexes interact with DNA in a nonintercalative mode. Experiments with supercoiled plasmid DNA show that both complexes can cleave DNA at neutral pH, where the L1 and L2 complexes display a similar reactivity. Conversely, the pH-dependence of their cleavage ability is remarkably different. The reactivity of the mononuclear complex, in fact, decreases with pH while that of the dinuclear one is enhanced at alkaline pH values. The efficiency of the two complexes in DNA cleavage at different pH values was elucidated by means of a quantum mechanics/molecular mechanics (QM/MM) study on the adducts between DNA and the different complexed species present in solution.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino, Firenze, Italy. carla.bazzicalupi@unifi.it
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzicalupi
authors.forename: Andrea
authors.initials: A
authors.lastname: Bencini
authors.forename: Claudia
authors.initials: C
authors.lastname: Bonaccini
authors.forename: Claudia
authors.initials: C
authors.lastname: Giorgi
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Simionato
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Barbara
authors.initials: B
authors.lastname: Valtancoli
mesh_terms: D018360:Crystallography, X-Ray; D053837:DNA Cleavage / Q000187:drug effects*; D015195:Drug Design; D006867:Hydrolases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046911:Macromolecular Substances / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D015032:Zinc / Q000737:chemistry*
chemical_list: D046911:Macromolecular Substances; D006867:Hydrolases; D015032:Zinc