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Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation
Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
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2016 (Engelska)Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, nr 6, s. 1255-1263Artikel i tidskrift (Refereegranskat) Published
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Abstract [en]

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.

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2016. Vol. 110, nr 6, s. 1255-1263
Nationell ämneskategori
Biofysik
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URN: urn:nbn:se:uu:diva-295568DOI: 10.1016/j.bpj.2016.02.016ISI: 000373487200008PubMedID: 27028636OAI: oai:DiVA.org:uu-295568DiVA, id: diva2:941262
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF)VetenskapsrådetTillgänglig från: 2016-06-22 Skapad: 2016-06-08 Senast uppdaterad: 2017-11-28

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