title: Adenosine/guanosine-3',5'-bis-phosphates as biocompatible and selective Zn2+-ion chelators. Characterization and comparison with adenosine/guanosine-5'-di-phosphate.
abstract: Although involved in various physiological functions, nucleoside bis-phosphate analogues and their metal-ion complexes have been scarcely studied. Hence, here, we explored the solution conformation of 2′-deoxyadenosine- and 2′-deoxyguanosine-3′,5′-bisphosphates, 3 and 4, d(pNp), as well as their Zn(2+)/Mg(2+) binding sites and binding-modes (i.e. inner- vs. outer-sphere coordination), acidity constants, stability constants of their Zn(2+)/Mg(2+) complexes, and their species distribution. Analogues 3 and 4, in solution, adopted a predominant Southern ribose conformer (ca. 84%), gg conformation around C4'-C5' and C5'-O5' bonds, and glycosidic angle in the anti-region (213-270°). (1)H- and (31)P-NMR experiments indicated that Zn(2+)/Mg(2+) ions coordinated to P5' and P3' groups of 3 and 4 but not to N7 nitrogen atom. Analogues 3 and 4 formed ca. 100-fold more stable complexes with Zn(2+)vs. Mg(2+)-ions. Complexes of 3 and 4 with Mg(2+) at physiological pH were formed in minute amounts (11% and 8%, respectively) vs. Zn(2+) complexes (46% and 44%). Stability constants of Zn(2+)/Mg(2+) complexes of analogues 3 and 4 (log KML(M) = 4.65-4.75/2.63-2.79, respectively) were similar to those of the corresponding complexes of ADP and GDP (log KML(M) = 4.72-5.10/2.95-3.16, respectively). Based on the above findings, we hypothesized that the unexpectedly low log K values of Zn(2+)-d(pNp) as compared to Zn(2+)-NDP complexes, are possibly due to formation of outer-sphere coordination in the Zn(2+)-d(pNp) complex vs. inner-sphere in the NDP-Zn(2+) complex, in addition to loss of chelation to N7 nitrogen atom in Zn(2+)-d(pNp). Indeed, explicit solvent molecular dynamics simulations of 1 and 3 for 100 ns supported this hypothesis.
authors: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar Ilan University, Ramat-Gan 52900, Israel. bilha.fischer@biu.ac.il.
authors: Alon Haim
authors: AH
authors: Sayer
authors: Eliav
authors: E
authors: Blum
authors: Dan Thomas
authors: DT
authors: Major
authors: Alexandra
authors: A
authors: Vardi-Kilshtain
authors: Bosmat
authors: B
authors: Levi Hevroni
authors: Bilha
authors: B
authors: Fischer
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000737:chemistry*; D001665:Binding Sites; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry; D055664:Electrochemical Techniques; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D015032:Zinc / Q000737:chemistry*
chemical_list: C523304:2'-deoxyadenosine-3',5'-diphosphate; D002614:Chelating Agents; D056831:Coordination Complexes; D007477:Ions; D006153:Guanosine Diphosphate; C065276:2'-deoxyguanosine 3',5'-diphosphate; D000244:Adenosine Diphosphate; D008274:Magnesium; D015032:Zinc