| 1. |
- Nordell, Pär, 1978, et al.
(författare)
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DNA Polymorphism as an Origin of Adenine-Thymine Tract Length-Dependent Threading Intercalation Rate
- 2008
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 130:44, s. 14651-14658
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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.
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| 2. |
- Nordell, Pär, 1978, et al.
(författare)
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Finding at-DNA--kinetic recognition of long adenine-thymine stretches by metal-ligand complexes.
- 2008
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Ingår i: Nucleic acids symposium series (2004). - 1746-8272. ; :52, s. 131-132
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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.
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| 3. |
- Nordell, Pär, 1978, et al.
(författare)
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Kinetic recognition of AT-rich DNA by ruthenium complexes
- 2007
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Ingår i: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 46:13, s. 2203-2206
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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.
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| 4. |
- Westerlund, Fredrik, 1978, et al.
(författare)
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Complex DNA binding kinetics resolved-by combined circular dichroism and luminescence analysis
- 2008
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 112:21, s. 6688-6694
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Tidskriftsartikel (refereegranskat)abstract
- We recently reported that ruthenium complexes, with general structure [μ-bidppz(bipy) 4 Ru 2 ] 4+ (B) or [μ-bidppz(phen) 4 Ru 2 ] 4+ (P) (bidppz = 11,11′-bi(dipyrido[3,2-a:2′,3′-c]phenazinyl)), show extreme kinetic selectivity for long AT tracts over mixed-sequence calf thymus DNA (ct-DNA), a selectivity that also varies markedly with the size (between B and P) and sense of chirality of the complex. Earlier studies, exploiting the great increase in luminescence intensity when the compound intercalates, have yielded complex kinetics indicating the presence of both first- and second-order processes. Even with a homogeneous DNA sequence, such as poly(dAdT) 2 , the luminescence kinetics generally requires more than a single exponential for a satisfactory fit. We here reveal that at least part of the complexity is a result of the extreme sensitivity of the effective quantum yield of the complexes, so that the luminescence trajectories also reflect subtle variations in the environment and binding geometry that the complex is sampling on its path to its final binding site. By monitoring the rearrangement process using circular dichroism (CD), we show that threading of both enantiomers of B and P into poly(dAdT) 2 is effectively a monoexponential process, as expected if the compounds are not affecting each other during the intercalation process. Thus, the complex luminescence trajectories may be explained by slow relaxations in the binding geometry (DNA conformation) and associated changes in the environment of the entering complexes. To further disentangle the intriguing features of the threading intercalation kinetics, and how they may depend on the flexibility and size of the ruthenium complexes, we have also designed and studied two new ruthenium complexes, [μ-dtpf(phen) 4 Ru 2 ] 4+ (F) (dtpf = 4,5,9,12,16,17,21,25- octaaza-23H-ditriphenyleno[2,3-b:2,3-h]fluorene), in which the bridging ligand is made totally rigid, and [μ-bidppz([12] aneS 4 ) 2 Ru 2 ] 4+ (S), which has less bulky, nonaromatic ancillary ligands. The threading of F into poly(dAdT) 2 , also found to be a monoexponential process, is about 3 times slower than for P, indicating that the flexibility of the bridging ligand is an important factor for the intercalation rate. Surprisingly, in contrast to all other compounds, S requires two exponentials to fit its binding kinetics as monitored by CD. Also surprisingly, in view of the smaller steric bulk, even the fastest phase is roughly 2 times slower for S than for B and P. Thus, not only the size of the ancillary ligand but also other properties that can influence the energy landscape of the threading path are rate-determining factors. With mixed-sequence ct-DNA, threading of B and that of P are both multiphasic processes when monitored with CD as well as with luminescence. The rate constants for threading into ct-DNA show much larger variations between complexes than for poly(dAdT) 2 , confirming earlier results based on luminescence data. © 2008 American Chemical Society.
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| 5. |
- Westerlund, Fredrik, 1978, et al.
(författare)
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Kinetic characterization of an extremely slow DNA binding equilibrium
- 2007
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 111:30, s. 9132-9137
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Tidskriftsartikel (refereegranskat)abstract
- We here exploit the recently reported thermodynamic preference for poly(dAdT)(2) over mixed-sequence calf thymus (ct) DNA of two binuclear ruthenium complexes, Delta Delta-[mu-bidppz(bipy)(4)Ru-2](4+) (B) and Delta Delta-[mu-bidppz(phen)(4)Ru-2](4+) (P), that bind to DNA by threading intercalation, to determine their intrinsic dissociation rates. After adding poly(dAdT)(2) as a sequestering agent to B or P bound to ct-DNA, the observed rate of change in luminescence upon binding to the polynucleotide reflects the rate of dissociation from the mixed sequence. The activation parameters for the threading and dissociation rate constants allow us for the first time to characterize the thermodynamics of the exceedingly slow threading intercalation equilibrium of B and P with ct-DNA. The equilibrium is found to be endothermic by 33 and 76 kJ/mol, respectively, and the largest part of the enthalpy difference between the complexes originates from the forward threading step. At physiological temperature (37 degrees C) B and P have dissociation half-lives of 18 and 38 h, respectively. This is to our knowledge the slowest dissociating noncovalently bound DNA-drug reported. SDS sequestration is the traditional method for determination of rate constants for cationic drugs dissociating from DNA. However, the rates may be severely overestimated for slowly dissociating molecules due to unwanted catalysis by the SDS monomers and micelles. Having determined the intrinsic dissociation rates with poly(dAdT)(2) as sequestering agent, we find that the catalytic effect of SDS on the dissociation rate may be up to a factor of 60, and that the catalysis is entropy driven. A simple kinetic model for the SDS concentration dependence of the apparent dissociation rate suggests an intermediate that involves both micelles and DNA-threaded complex.
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| 6. |
- Wilhelmsson, Marcus, 1974, et al.
(författare)
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Meso stereoisomer as a probe of enantioselective threading intercalation of semirigid ruthenium complex [µ-(11,11'-bidppz)(phen)4Ru2]4
- 2003
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 107:42, s. 11784-11793
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Tidskriftsartikel (refereegranskat)abstract
- Upon interaction with calf thymus DNA the Lambda,Lambda-enantiomer of the semirigid binuclear ruthenium complex [mu-(11, 11'-bidppz)(phen)(4)Ru-2](4+) has previously been shown to reorganize from an initial groove bound geometry into an intercalative binding mode, threading one of its bulky Ru(phen)(2) moieties through the core of the DNA. We have now found that all three stereoisomers, Delta,Delta; Lambda,Lambda; and Delta,Lambda (meso), are intercalated in their final modes of binding to calf thymus DNA, poly(dA-dT)(2), poly(dG-dC)(2), as well as poly(dI-dC)(2) indicated by linear dichroism, circular dichroism, and luminescence. For all three stereoisomers, studied in detail with poly(dA-dT)(2), the bridging bidppz ligand is intercalated in anti conformation, leaving one Ru(phen)(2) Moiety in each groove. This final binding geometry is characterized by a distinct clockwise roll of the Ru(phen)(2) moiety in the minor groove, similar to the roll earlier observed for the dppz ligand in [Ru(phen)(2)dppz](2+). Using the meso stereoisomer as an enantioselective probe, it is shown that the Lambda moiety prefers to insert itself deeply into the minor groove while the Delta moiety, in the major groove, is somewhat displaced from the center of the DNA helix. The preceding, metastable bound geometries are concluded to be in the major groove for calf thymus DNA, poly(dG-dC)(2), and poly(dI-dC)(2), with the Delta,Delta form displaying an angle of the bidppz bridge relative the DNA helix axis of about 50degrees, whereas the corresponding angles for the meso- and Lambda,Lambda-forms in calf thymus DNA are around 65degrees, suggesting an orientation in the groove more parallel to the bases. By contrast, in poly(dA-dT)(2) none of the stereoisomers exhibits any distinguishable initial groove binding mode, but all seem to bind by threading intercalation directly.
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| 7. |
- Feng, Bobo, 1987, et al.
(författare)
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DNA strand exchange catalyzed by molecular crowding in PEG solutions
- 2010
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 46:43, s. 8231-8233
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Tidskriftsartikel (refereegranskat)abstract
- DNA strand exchange is catalyzed by molecular crowding and hydrophobic interactions in concentrated aqueous solutions of polyethylene glycol, a discovery of relevance for understanding the function of recombination enzymes and with potential applications to DNA nanotechnology.
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| 8. |
- Feng, Bobo, 1987, et al.
(författare)
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Evidence for hydrophobic catalysis of DNA strand exchange
- 2015
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1364-548X .- 1359-7345. ; 51:34, s. 7390-7392
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Tidskriftsartikel (refereegranskat)abstract
- The catalytic role of hydrophobic co-solutes in DNA strand exchange is demonstrated by FRET kinetics. Two mechanisms that contribute to this are base stacking destabilisation and nucleation-promoted DNA strand invasion. We propose that hydrophobic catalysis is involved in the strand-exchange activity of recombination enzymes.
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| 9. |
- Feng, Bobo, 1987, et al.
(författare)
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Hydrophobic catalysis and a potential biological role of DNA unstacking induced by environment effects
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:35, s. 17169-17174
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Tidskriftsartikel (refereegranskat)abstract
- Hydrophobic base stacking is a major contributor to DNA double-helix stability. We report the discovery of specific unstacking effects in certain semihydrophobic environments. Water-miscible ethylene glycol ethers are found to modify structure, dynamics, and reactivity of DNA by mechanisms possibly related to a biologically relevant hydrophobic catalysis. Spectroscopic data and optical tweezers experiments show that base-stacking energies are reduced while base-pair hydrogen bonds are strengthened. We propose that a modulated chemical potential of water can promote “longitudinal breathing” and the formation of unstacked holes while base unpairing is suppressed. Flow linear dichroism in 20% diglyme indicates a 20 to 30% decrease in persistence length of DNA, supported by an increased flexibility in single-molecule nanochannel experiments in poly(ethylene glycol). A limited (3 to 6%) hyperchromicity but unaffected circular dichroism is consistent with transient unstacking events while maintaining an overall average B-DNA conformation. Further information about unstacking dynamics is obtained from the binding kinetics of large thread-intercalating ruthenium complexes, indicating that the hydrophobic effect provides a 10 to 100 times increased DNA unstacking frequency and an “open hole” population on the order of 10−2 compared to 10−4 in normal aqueous solution. Spontaneous DNA strand exchange catalyzed by poly(ethylene glycol) makes us propose that hydrophobic residues in the L2 loop of recombination enzymes RecA and Rad51 may assist gene recombination via modulation of water activity near the DNA helix by hydrophobic interactions, in the manner described here. We speculate that such hydrophobic interactions may have catalytic roles also in other biological contexts, such as in polymerases.
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| 10. |
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