| 1. |
- Andersson, Johanna, 1983, et al.
(författare)
-
Lifetime Heterogeneity of DNA-Bound dppz Complexes Originates from Distinct Intercalation Geometries Determined by Complex-Complex Interactions
- 2013
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 52:2, s. 1151-1159
-
Tidskriftsartikel (refereegranskat)abstract
- Despite the extensive interest in structurally explaining the photophysics of DNA-bound [Ru(phen)(2)dppz](2+) and [Ru(bpy)(2)dppz](2+), the origin of the two distinct emission lifetimes of the pure enantiomers when intercalated into DNA has remained elusive. In this report, we have combined a photophysical characterization with a detailed isothermal titration calorimetry study to investigate the binding of the pure Delta and Lambda enantiomers of both complexes with [poly(dAdT)](2). We find that a binding model with two different binding geometries, proposed to be symmetric and canted intercalation from the minor groove, as recently reported in high-resolution X-ray structures, is required to appropriately explain the data. By assigning the long emission lifetime to the canted binding geometry, we can simultaneously fit both calorimetric data and the binding-density-dependent changes in the relative abundance of the two emission lifetimes using the same binding model. We find that all complex complex interactions are slightly unfavorable for Delta-[Ru(bpy)(2)dppz](2+), whereas interactions involving a complex canted away from a neighbor are favorable for the other three complexes. We also conclude that Delta-[Ru(bpy)(2)dppz](2+) preferably binds isolated, Delta-[Ru(phen)(2)dppz](2+) preferably binds as duplets of canted complexes, and that all complexes are reluctant to form longer consecutive sequences than triplets. We propose that this is due to an interplay of repulsive complex complex and attractive complex-DNA interactions modulated by allosteric DNA conformation changes that are largely affected by the nature of the ancillary ligands.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Nordell, Pär, 1978, et al.
(författare)
-
DNA Polymorphism as an Origin of Adenine-Thymine Tract Length-Dependent Threading Intercalation Rate
- 2008
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 130:44, s. 14651-14658
-
Tidskriftsartikel (refereegranskat)abstract
- Binuclear ruthenium complexes that bind DNA by threading intercalation have recently been found to exhibit an exceptional kinetic selectivity for long polymeric adenine-thymine (AT) DNA. A series of oligonucleotide hairpin duplexes containing a central tract of 6-44 alternating AT base pairs have here been used to investigate the nature of the recognition mechanism. We find that, above a threshold AT tract length corresponding to one helix turn of B-DNA, a dramatic increase in threading intercalation rate occurs. In contrast, such length dependence is not observed for rates of unthreading. Intercalation by any mechanism that depends on the open end of the hairpin was found not to be important in the series of oligonucleotides used, as verified by including in the study a hairpin duplex cyclized by a copper-catalyzed "click" reaction. Our observations are interpreted in terms of a conformational pre-equilibrium, determined by the length of the AT tract. We finally find that mismatches or loops in the oligonucleotide facilitate the threading process, of interest for the development of mismatch-recognizing probes. © 2008 American Chemical Society.
|
|
| 6. |
- Nordell, Pär, 1978, et al.
(författare)
-
Finding at-DNA--kinetic recognition of long adenine-thymine stretches by metal-ligand complexes.
- 2008
-
Ingår i: Nucleic acids symposium series (2004). - 1746-8272. ; :52, s. 131-132
-
Tidskriftsartikel (refereegranskat)abstract
- High selectivity for long AT sequences can be attained by kinetically controlled DNA threading intercalation by binuclear ruthenium(II) complexes. The rate of intercalation is strongly correlated to the number of consecutive AT basepairs, being up to 2500 times faster with an AT polymer compared to mixed-sequence DNA.
|
|
| 7. |
- Nordell, Pär, 1978, et al.
(författare)
-
Kinetic recognition of AT-rich DNA by ruthenium complexes
- 2007
-
Ingår i: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 46:13, s. 2203-2206
-
Tidskriftsartikel (refereegranskat)abstract
- (Figure Presented) Finding AT tracts: High selectivity for long AT sequences can be attained through kinetically controlled DNA threading intercalation by binuclear ruthenium (II) complexes (see picture). The rate of intercalation is strongly correlated to the number of consecutive AT base pairs and is up to 2500-times higher with poly-(dAdT) 2 than with mixed-sequence DNA. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.
|
|
| 8. |
- Nordell, Pär, 1978
(författare)
-
Kinetic Recognition of Nucleic Acids - Studies on the DNA Binding Selectivity of Threading Ruthenium Complexes
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite the great progress in our understanding of DNA during the past half-century, there are many important aspects of its chemical and biological role yet to be explored. The principles by which it selectively interacts with other molecules have attracted much interest due to the relevance for fundamental cellular processes, as well as for the development of diagnostic probes and effective pharmaceutical agents. This Thesis describes the study of the process in which a planar aromatic moiety, hindered by bulky substituents on both ends, is threaded through the DNA double helix. Dumb-bell shaped binuclear ruthenium complexes of the type [µ-(bidppz)(L)4Ru2]4+, L = phenanthroline (P) or bipyridine (B) bind upon mixing with DNA rapidly on the outside of the double-helix, after which they rearrange to an intercalated binding mode. Passing one large metal centre between the strands requires large transient distortions of the duplex, leading to extremely slow binding kinetics that is sensitive to DNA sequence as well as ruthenium complex structure. This work has (1) addressed the mechanisms behind this “kinetic recognition” and (2) identified potential DNA structural targets. Both enantiomers of chiral analogues P and B require several hours at 50°C to rearrange to the threaded binding mode in mixed sequence DNA. Alternating AT polymers, on the other hand, are intercalated within a few minutes at room temperature. The ratio between the forward rates is estimated to vary between 65 (ΛΛ-P) and 2500 (ΛΛ-B). Studies with AT-tract oligonucleotides show that more than one complete helix turn of AT-DNA is required for efficient threading, a stretch considerably larger than the complexes themselves. Long AT-stretches are however not the only kinetically favored targets; subjecting mixed sequence DNA to negative supercoiling can increase the threading rate by as much as two orders of magnitude. Accelerated intercalation is also observed with partially unpaired DNA. Dissociation from mixed sequence DNA displays half-lives of up to 38 h at physiological temperature, the slowest release reported for a reversibly bound agent. The selectivity demonstrated by the binuclear ruthenium complexes in vitro make them interesting in the development of new agents against parasitic protozoa with AT-rich DNA.
|
|
| 9. |
- Nordell, Pär, 1978, et al.
(författare)
-
Mechanism of DNA Threading Intercalation of Binuclear Ru Complexes: Uni- or Bimolecular Pathways Depending on Ligand Structure and Binding Density
- 2005
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 127:27, s. 9670-9671
-
Tidskriftsartikel (refereegranskat)abstract
- In the long succession of small transition-metal compounds interacting reversibly with DNA, semirigid binuclear ruthenium complexes stand out by displaying exceptionally slow binding kinetics. To reach the final intercalated state, one of the bulky metal centers has to be threaded through the base stack, leading to a high level of structural discrimination. This makes the idea of utilizing binuclear complexes interesting in applications involving DNA sequence or conformation recognition. The finding that threading intercalation of the two structural analogues, Λ,Λ-[μ-(11,11‘-bidppz)X4Ru2]4+, X = 2,2‘-bipyridine (Λ,Λ-B4) and X = 1,10‘-phenanthroline (Λ,Λ-P4), into poly(dA-dT)2 can be described by surprisingly simple rate laws encouraged more extensive studies and analysis of these two systems. Kinetic measurements at different [basepair]/[complex] ratios show that Λ,Λ-B4 intercalates via a pseudo-first-order mechanism independent of binding density, whereas Λ,Λ-P4 displays a gradual transition from apparent first- to second-order kinetics when decreasing the [basepair]/[complex] mixing ratio. By employing the probabilistic method of McGhee and von Hippel, a rate law based on a supposed mechanism has been globally fitted and numerically integrated to describe threading of Λ,Λ-P4. In contrast to Λ,Λ-B4, the first-order mechanism of this analogue appears to require a long stretch of nonthreaded DNA. The results show that ancillary ligand structures indeed affect the mechanism of DNA threading, demonstrating the potential use of semirigid binuclear ruthenium complexes to target DNA.
|
|
| 10. |
- Nordell, Pär, 1978, et al.
(författare)
-
Supercoil-Accelerated DNA Threading Intercalation
- 2009
-
Ingår i: Biochemistry. - 1520-4995 .- 0006-2960. ; 48:7, s. 1442-1444
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of DNA supercoiling on a sterically very demanding threading intercalation process is here investigated. We find that the threading rate of a dimeric ruthenium complex into a negatively supercoiled plasmid at low binding density is two orders of magnitude higher than into the cleaved linear form. Further saturation is however, in comparison to the linear DNA, kinetically hampered. We also observe that threading kinetics correlates with the inhibition of luciferase expression from the plasmid construct. The results show how the target torsional strain can function as control of DNA threading kinetics and gene expression efficiency.
|
|
