The assembly of DNA threading intercalation complexes quantified from nano-mechanical single-molecule measurements

Permanent URL: http://hdl.handle.net/2047/D20199725
Title:
The assembly of DNA threading intercalation complexes quantified from nano-mechanical single-molecule measurements
Creator:
Almaqwashi, Ali A. (Author)
Contributor:
Williams, Mark C. (Advisor)
Sage, Timothy (Committee member)
Stepanyants, Armen (Committee member)
Wanunu, Meni (Committee member)
Language:
English
Publisher:
Boston, Massachusetts : Northeastern University, 2015
Date Accepted:
December 2015
Date Awarded:
January 2016
Type of resource:
Text
Genre:
Dissertations
Format:
electronic
Digital origin:
born digital
Abstract/Description:
There is a wide range of applications for DNA intercalation, a DNA-ligand assembly process in which small planar aromatic molecules are reversibly inserted between adjacent DNA base pairs. In particular, the recently developed dumbbell-shaped DNA threading intercalators, binuclear ruthenium complexes, represent the next order of structural complexity relative to simple intercalators, and can provide significant new insights into the molecular mechanisms that govern DNA-ligand intercalation. This model intercalating system involves passing the end of the dumbbell through broken base pairs before reaching the equilibrium intercalation state, which induces dynamic DNA structural distortion and exhibits equilibrium and kinetics properties desirable for DNA-targeting therapeutics. Single-molecule force spectroscopy using optical tweezers can provide precise measurements, enabling comprehensive investigation of diverse DNA assemblies. From efficiently controlled nanomechanical single-molecule measurements, force spectroscopy can determine the kinetics of DNA-ligand assembly and disassembly and the intercalation affinity as well as reveal the magnitude of equilibrium and dynamic structural deformations of the DNA-ligand complex. This work examines several structural modifications aimed toward optimizing DNA threading intercalation by binuclear ruthenium complexes. The results demonstrate robust DNA structural recognition of DNA threading intercalators. Essential molecular aspects of DNA-ligand intercalation are characterized, including the reshaping of the threading energy landscape due the modifications of each structural subunit. The findings of this work will hopefully guide the rational design of intercalating molecular systems which are optimized for DNA-targeted synthetic drugs, optical probes, or DNA-integrated self-assembly processes.
Subjects and keywords:
DNA intercalators
DNA-ligand assembly
single molecule
structural dynamics
DNA-ligand interactions
DNA -- Structure
Ligands (Biochemistry)
Ligand binding (Biochemistry)
Aromaticity (Chemistry)
Optical tweezers
DOI:
https://doi.org/10.17760/D20199725
Permanent Link:
http://hdl.handle.net/2047/D20199725
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