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Dissecting the Dyna...
Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation
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- Almaqwashi, A. A. (författare)
- Northeastern University,Northeastern Univ, Dept Phys, Boston, MA 02115 USA.
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- Andersson, Johanna, 1983 (författare)
- Uppsala universitet,Institutionen för kemi - BMC,Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.,Chalmers tekniska högskola,Chalmers University of Technology
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- Lincoln, Per, 1958 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology,Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
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- Rouzina, I. (författare)
- Ohio State University,Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA.
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- Westerlund, Fredrik, 1978 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology,Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.
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- Williams, M. C. (författare)
- Northeastern University,Northeastern Univ, Dept Phys, Boston, MA 02115 USA.
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Northeastern University Northeastern Univ, Dept Phys, Boston, MA 02115 USA (creator_code:org_t)
- Elsevier BV, 2016
- 2016
- Engelska.
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 110:6, s. 1255-1263
- Relaterad länk:
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http://dx.doi.org/10...
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http://www.cell.com/...
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https://doi.org/10.1...
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https://research.cha...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- DNA intercalators that have high affinity and slow kinetics are developed for potential DNA-targeted therapeutics. Although many natural intercalators contain multiple chiral subunits, only intercalators with a single chiral unit have been quantitatively probed. Dumbbell-shaped DNA threading intercalators represent the next order of structural complexity relative to simple intercalators, and can provide significant insights into the stereoselectivity of DNA-ligand intercalation. We investigated DNA threading intercalation by binuclear ruthenium complex [mu-dppzip(phen)(4)Ru-2](4+) (Piz). Four Piz stereoisomers are defined by the chirality of the intercalating subunit (Ru(phen)(2)dppz) and the distal subunit (Ru(phen)(2)ip), respectively, each of which can be either right-handed (Delta) or left-handed (Lambda). We used optical tweezers to measure single DNA molecule elongation due to threading intercalation, revealing force-dependent DNA intercalation rates and equilibrium dissociation constants. The force spectroscopy analysis provided the zero-force DNA binding affinity, the equilibrium DNA-ligand elongation Delta x(eq), and the dynamic DNA structural deformations during ligand association x(on) and dissociation x(off). We found that Piz stereoisomers exhibit over 20-fold differences in DNA binding affinity, from a K-d of 27 +/- 3 nM for (Delta,Lambda)-Piz to a K-d of 622 +/- 55 nM for (Lambda,Delta)-Piz. The striking affinity decrease is correlated with increasing Delta x(eq) from 0.30 +/- 0.02 to 0.48 +/- 0.02 nm and x(on) from 0.25 +/- 0.01 to 0.46 +/- 0.02 nm, but limited x(off) changes. Notably, the affinity and threading kinetics is 10-fold enhanced for right-handed intercalating subunits, and 2- to 5-fold enhanced for left-handed distal subunits. These findings demonstrate sterically dispersed transition pathways and robust DNA structural recognition of chiral intercalators, which are critical for optimizing DNA binding affinity and kinetics.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
Nyckelord
- single dna
- actinomycin-d
- binuclear ruthenium complex
- molecule
- optical tweezers
- binding-kinetics
- noncooperative binding
- equilibrium
- affinity
- force spectroscopy
- Biophysics
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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