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Structure-Activity Studies on bPNA Triplex Hybridization with DNA and RNA

Rundell, Sarah
http://rave.ohiolink.edu/etdc/view?acc_num=osu1629668708970764

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Chemistry.
Our lab has utilized bPNAs and small molecules to bind with DNA or RNA and have shown the versatility of melamine-based moieties, though the detailed structural characterization of triplex structure remains elusive. We describe structure-function studies on the bPNA “tripeptide” scaffold that centers on variation of the non-base tripling residue to explore the impact of secondary structure propensity on hybridization with DNA and RNA. To investigate the impact of the central X-residue on hybridization structure, we focused on simplified 4M tripeptide bPNAs and varied the identity of the central X amino acid residue. We had the goal of identifying a more compact and synthetically accessible bPNA which revealed that the tripeptides hybridization is highly tolerant of changes in the central residue. Notably, binding to T-rich DNAs results in a hybrid structure that is much more stable than the analogous RNA complex. With this success, we looked to further minimize the scaffold via stereoisomer synthesis and reduction of backbone entropy by cyclization. We particularly focused on completely removing the central X residue yielding a dipeptide and further looked at backbone cyclization yielding diketopiperazines (DKP). The changes to stereochemistry and backbone constraint had significant impact on the hybridization to DNA and RNA especially the DKP exhibiting the highest stability. Further studies aimed to extract information from the addition of the D-Lys giving derivatives using the k2M enantiomer to evaluate the impact it has backbone stereochemistry on triplex hybridization. The D, L linear peptides show an increase in stability while the D, L diketopiperazine was poorly effective in hybridization with DNA with hybridization to RNA undetectable. This flipping configuration indicates high sensitivity to backbone conformation. Most notable in our studies was the bPNAs consistently binding to DNA with greater thermal stability than RNA. We looked to focus on the role of the bases to investigate the origin of the biophysical difference by replacing thymine with uracil on a DNA backbone. We observed significant loss of thermal stability from replacing more uracils into the DNA suggesting methyl stacking plays a role in hybrid stability. Based on our findings, this suggests the sugar conformation is of B-form in DNA is more favorable than A-form in RNA. Thus, we propose new synthetic strategies to improve bPNA RNA binding. In summary, these findings demonstrate the tolerance of DNA hybridization with 4M bPNAs and RNAs weak hybridization. We dive into how the backbone of the bPNA affects hybridization looking into tripeptides with a B-strand like conformation, dipeptides, constraining dipeptides by cyclizing the backbone, and introducing the k2M enantiomer to evaluate the impact of bPNA backbone stereochemistry. Notably, we turn our attention to the interaction of the bases in hybridization, with focus on methyl stacking leading to hybrid stability, and therefore proposing new synthetic strategies.
Dennis Bong (Advisor)
Ross Dalbey (Committee Member)
Dehua Pei (Committee Member)
210 p.
Biochemistry; Chemistry
bPNA RNA melamine triplex hybridization

Recommended Citations

Citations

  • Rundell, S. (2021). Structure-Activity Studies on bPNA Triplex Hybridization with DNA and RNA [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1629668708970764

    APA Style (7th edition)

  • Rundell, Sarah. Structure-Activity Studies on bPNA Triplex Hybridization with DNA and RNA. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1629668708970764.

    MLA Style (8th edition)

  • Rundell, Sarah. "Structure-Activity Studies on bPNA Triplex Hybridization with DNA and RNA." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1629668708970764

    Chicago Manual of Style (17th edition)

osu1629668708970764
46
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This open access ETD is published by The Ohio State University and OhioLINK.