A computational study of DNA four-way junctions and their significance to DNA nanotechnology
Author(s)Adendorff, Matthew Ralph
Massachusetts Institute of Technology. Department of Biological Engineering.
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The field of DNA nanotechnology has rapidly evolved over the past three decades, reaching a point where researchers can conceive of and implement both bioinspired and biomimetic devices using the programmed self-assembly of DNA molecules. The sophisticated natural systems that these devices seek to interrogate and to imitate have Angstrom-level organizational precision, however, and the nanotechnology community faces the challenge of fine-tuning their design principles to match. A necessity for achieving this level of spatial control is an understanding of the atomic-level physico-chemical interactions and temporal dynamics inherent to fundamental structural motifs used for nanodevice design. The stacked configurational isomers of four-way junctions, the motif on which DNA nanotechnology was founded, are the focus of this work; initially in isolation and then as part of larger DNA nano-assemblies. The first study presented here investigates the impact of sequence on the structure, stability, and flexibility of these junction isomers, along with their canonical B-form duplex, nicked-duplex and single cross-over topological variants. Using explicit solvent and counterion molecular dynamics simulations, the base-pair level interactions that influence experimentally-observed conformational state preferences are interrogated and free-energy calculations provide a detailed theoretical picture of isomerization thermodynamics. Next, the synergy of single molecule imaging, computational modelling, and a novel enzymatic assay is exploited to characterize the three-dimensional structure and catalytic function of a DNA tweezer-actuated nanoreactor. The analyses presented here show that rational redesign of the four-way junctions in the device enables the tweezers to be more completely and uniformly closed, while the sequence-level design strategies explored in this study provide guidelines for improving the performance of DNA-based structures. Finally, MD simulations are used to inform finite-element method coarse-grained models for the ground-state structure determination and equilibrium Brownian Dynamics of large-scale DNA origamis. Together, this thesis presents a set of guidelines for the rational design of nanodevices comprising arrays of constrained four-way junctions.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 161-180).
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering.; Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology