Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation

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Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation

Almaqwashi, A. A. (author): Northeastern University,Northeastern Univ, Dept Phys, Boston, MA 02115 USA.

Andersson, Johanna, 1983 (author): Uppsala universitet,Institutionen för kemi - BMC,Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.,Chalmers tekniska högskola,Chalmers University of Technology

Lincoln, Per, 1958 (author): Chalmers tekniska högskola,Chalmers University of Technology,Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.

Rouzina, I. (author): Ohio State University,Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA.

Westerlund, Fredrik, 1978 (author): Chalmers tekniska högskola,Chalmers University of Technology,Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.

Williams, M. C. (author): 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
English.
In: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 110:6, s. 1255-1263

Related links:: http://dx.doi.org/10...; show more...; http://www.cell.com/...; https://doi.org/10.1...; https://research.cha...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)

Keyword

single dna
actinomycin-d
binuclear ruthenium complex
molecule
optical tweezers
binding-kinetics
noncooperative binding
equilibrium
affinity
force spectroscopy
Biophysics

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By the author/editor: Almaqwashi, A. A ...; Andersson, Johan ...; Lincoln, Per, 19 ...; Rouzina, I.; Westerlund, Fred ...; Williams, M. C.

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biophysics

Articles in the publication: Biophysical Jour ...

By the university: Chalmers University of Technology; Uppsala University

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