Date of Award

Spring 5-2022

Document Type


Degree Name

Doctor of Philosophy (PhD)


Chemistry & Biochemistry



Committee Director

Craig A. Bayse

Committee Member

Alvin A. Holder

Committee Member

Jennifer L. Poutsma

Committee Member

Erin B. Purcell

Committee Member

Daniel J. Barshis


Metal ions have a myriad of biological functions from structural stability to enzymatic (de)activation and metabolic electron transfer. Redox-active metals also mediate the formation of reactive oxygen species which may either cause oxidative damage or protect cellular components. Computational modeling is used here to investigate the role of (1) metal-ion binding to antimicrobial peptides, (2) metal-ion removal and disulfide formation on zinc finger (ZF) proteins, and (3) coordination of thiones/selones for the prevention of metal-mediated redox damage.

Piscidins, natural-occurring antimicrobial peptides, efficiently kill bacteria by targeting their membranes. Their efficacy is enhanced in vitro by metal-binding and the presence of membrane-destabilizing oxidized phospholipids (oxPLs). Molecular dynamics (MD) simulations are used to model insertion of Ni2+-bound piscidins 1 (P1:Ni2+) and 3 (P3:Ni2+) into lipid bilayers in the presence and absence of oxPLs. Metallation promotes deeper peptide insertion in the membrane, and P1:Ni2+ is suggested to interact more with anionic lipid headgroups in the presence of oxPLs.

The release of Zn2+ from ZF proteins through oxidation of the cysteine thiolates is associated with inhibition of viral replication, disruption of cancer gene expression, and DNA repair preventing tumor growth. Multi-microsecond MD simulations were performed to examine the effect of cysteine oxidation on the ZF456 fragment of transcription factor IIIA and its complex with 5S RNA. Upon oxidation in the absence of RNA, the individual ZF domains unfold yielding a globular ZF456 peptide. Oxidation of the RNA-bound ZF456 peptide disrupts key hydrogen bonding interactions between ZF5/ZF6 and 5S RNA.

The antioxidant properties of sulfur and selenium compounds prevent metal-mediated (i.e., Fenton chemistry) oxidative damage. The effect of the coordination of sulfur/selenium derivatives of imidazolidinone (thiones/selones) on the electronic structure and reduction potential of Fe2+ ions solvated or coordinated to guanine are examined using density functional theory. The highest occupied molecular orbital (HOMO) for the Fe(II)-aqua complex is metal-centered but localized on the nucleobase in the Fe2+-guanine complex. Complexation of the thione/selone shifts the HOMO to the sulfur/selenium center suggesting a mechanism for protection of DNA by sacrificial oxidation of the sulfur/selenium ligand.


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