Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers
Artikel i vetenskaplig tidskrift, 2022

Small-molecule DNA-binding drugs have shown promising results in clinical use against many types of cancer. Understanding the molecular mechanisms of DNA binding for such small molecules can be critical in advancing future drug designs. We have been exploring the interactions of ruthenium-based small molecules and their DNA-binding properties that are highly relevant in the development of novel metal-based drugs. Previously we have studied the effects of the right-handed binuclear ruthenium threading intercalator ΔΔ-[μ-bidppz(phen)4Ru2]4+, or ΔΔ-P for short, which showed extremely slow kinetics and high-affinity binding to DNA. Here we investigate the left-handed enantiomer ΛΛ-[μ-bidppz(phen)4Ru2]4+, or ΛΛ-P for short, to study the effects of chirality on DNA threading intercalation. We employ single-molecule optical trapping experiments to understand the molecular mechanisms and nanoscale structural changes that occur during DNA binding and unbinding as well as the association and dissociation rates. Despite the similar threading intercalation binding mode of the two enantiomers, our data show that the left-handed ΛΛ-P complex requires increased lengthening of the DNA to thread, and it extends the DNA more than double the length at equilibrium compared with the right-handed ΔΔ-P. We also observed that the left-handed ΛΛ-P complex unthreads three times faster than ΔΔ-P. These results, along with a weaker binding affinity estimated for ΛΛ-P, suggest a preference in DNA binding to the chiral enantiomer having the same right-handed chirality as the DNA molecule, regardless of their common intercalating moiety. This comparison provides a better understanding of how chirality affects binding to DNA and may contribute to the development of enhanced potential cancer treatment drug designs.


Adam A. Jabak

Bridgewater State University

Nicholas Bryden

Bridgewater State University

Fredrik Westerlund

Chalmers, Biologi och bioteknik, Kemisk biologi

Per Lincoln

Chalmers, Kemi och kemiteknik, Kemi och biokemi

M. J. McCauley

Northeastern University

I. Rouzina

Ohio State University

Mark C. Williams

Northeastern University

T. Paramanathan

Bridgewater State University

Biophysical Journal

0006-3495 (ISSN) 1542-0086 (eISSN)

Vol. 121 19 3745-3752


Biokemi och molekylärbiologi

Annan medicinsk grundvetenskap

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)





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