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Quantitative Modeling of DNA Systems

Crocker, Kyle A
http://rave.ohiolink.edu/etdc/view?acc_num=osu1615218448408495

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Physics.
Here I develop computationally efficient quantitative models to describe the behavior of DNA-based systems. DNA is of fundamental biological importance, and its physical properties have been harnessed for technological applications. My work involves each of these aspects of DNA function, and thus provides broad insight into this important biomolecule. First, I examine how DNA mismaches are repaired in the cell. Protein complexes involved in DNA mismatch repair appear to diffuse along dsDNA in order to locate a hemimethylated incision site via a dissociative mechanism. I study the probability that these complexes locate a given target site via a semi-analytic, Monte Carlo calculation that tracks the association and dissociation of the complexes. I compare such probabilities to those obtained using a non-dissociative diffusive scan, and determine that for experimentally observed diffusion constants, search distances, and search durations in vitro, both search mechanisms are highly efficient for a majority of hemimethylated site distances. I then examine the space of physically realistic diffusion constants, hemimethylated site distances, and association lifetimes and determine the regions in which dissociative searching is more or less efficient than non-dissociative searching. I conclude that the dissociative search mechanism is advantageous in the majority of the physically realistic parameter space, suggesting that the dissociative search mechanism confers an evolutionary advantage. I then turn to synthetic DNA structures, initially focusing on a composite DNA nano-device. In particular, manipulation of temperature can be used to actuate DNA origami nano-hinges containing gold nanoparticles. I develop a physical model of this system that uses partition function analysis of the interaction between the nano-hinge and nanoparticle to predict the probability that the nano-hinge is open at a given temperature. The model agrees well with experimental data and predicts experimental conditions that allow the actuation temperature of the nano-hinge to be tuned over a range of temperatures from 30oC to 45oC. Additionally, the model reveals surprising physical constraints on the system. This combination of physical insight and predictive potential is likely to inform future designs that integrate nanoparticles into dynamic DNA origami structures. Furthermore, our modeling approach could be expanded to consider the incorporation, stability, and actuation of other types of functional elements or actuation mechanisms integrated into nucleic acid devices. Finally, I use quantitative modeling to reveal the ability of a DNA origami nano-hinge to apply forces on biomolecules. In particular, DNA overhangs near the vertex ("struts") of a nano-hinge are used to strongly bias the hinge angle distribution toward small angles. Partition function based models reveal that the global hinge structure can apply a force of more than 20 pN on the struts. Hinges with these struts are capable of inducing a buckling conformation in double-stranded DNA incorporated into the ends of the hinge arms in a way that is predicted well by a polymer-based model. Furthermore, manipulation of structural details the vertex of these hinges can be used to create hinges with different angular distributions. Modeling predicts that such distributions can be leveraged to bias nucleosomes into desired unwrapping states. I therefore demonstrate the utility of these nano-hinges for experimental applications in molecular biophysics. In general, my work suggests a methodological framework by which the macroscopic behavior of complex, designed DNA systems may be accurately predicted in a computationally efficient manner. This framework involves (1) the design of such devices such that a small number of high leverage DNA strands control the behavior, (2) a calibration in which the average behavior of the bulk of the devices is treated as a module and determined empirically, and (3) a thermodynamic model in which the interactions between the high leverage strands and the bulk module is described physically. In what follows, I illustrate the utility of this approach for a specific system, a DNA nano-hinge.
Ralf Bundschuh, PhD (Advisor)
Carlos Castro, PhD (Committee Member)
Michael Poirier, PhD (Committee Member)
Hirata Christopher , PhD (Committee Member)
169 p.
Biophysics; Nanotechnology; Physics; Polymers; Theoretical Physics
DNA; quantitative modeling; computational biology; thermodynamics; DNA mismatch repair; statistical physics; DNA origami; DNA nanotechnology; nucleosome; MutS; MutL; MutH

Recommended Citations

Citations

  • Crocker, K. A. (2021). Quantitative Modeling of DNA Systems [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1615218448408495

    APA Style (7th edition)

  • Crocker, Kyle. Quantitative Modeling of DNA Systems. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1615218448408495.

    MLA Style (8th edition)

  • Crocker, Kyle. "Quantitative Modeling of DNA Systems." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1615218448408495

    Chicago Manual of Style (17th edition)

osu1615218448408495
144
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This open access ETD is published by The Ohio State University and OhioLINK.
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