Date of Award

Summer 2021

Document Type


Degree Name

Doctor of Philosophy (PhD)


Chemistry & Biochemistry



Committee Director

Craig Bayse

Committee Member

Erin Purcell

Committee Member

Alvin Holder

Committee Member

Jennifer Poutsma

Committee Member

Jing He


Thyroid hormones (THs) in mammalian tissues are crucial for development and maintaining metabolic homeostasis. Iodothyronine deiodinases (Dios) remove iodines from THs by a selenocysteine (Sec) residue, which either activates or inactivates them. Halogen bonding (XB) has been proposed to describe the interaction between the Se and I atoms of the T4-Dio complex. Disruption of TH homeostasis by xenobiotics, such as polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can cause deleterious effects on the endocrine system. Experimental studies have indicated that PBDEs and PCBs could disrupt TH homeostasis by inhibiting Dio through XB formation. However, no current quantitative study exists that compares the relative strengths of PBDE and PCB XB strengths. Trends in XB interactions of a small model of the active site (MeSe-) with THs and potential inhibitors PBDEs and PCBs are analyzed using density functional theory (DFT). In agreement with trends in XB, XB favorability follows in the order of THs > PBDEs > PCBs (i.e., I > Br > Cl). Highly brominated PBDEs show similar interaction energies to THs, suggesting possible inhibition and debromination of these compounds.

Schweizer et al. solved the crystal structure of the monomeric catalytic domain of Dio3. However, Dio3 must dimerize in order to perform catalytic deiodination, and no structural data currently exists regarding a Dio3 dimer. A debate between two groups has been ongoing in the literature regarding how Dio3 undergoes dimerization. Proposed Dio3 dimer structures by Sagar and Schweizer may be attributed to the observance of A-type and B-type dimers within peroxiredoxins (Prxs). Sequential comparisons using Clustal Omega of Dio3 to known A-type and B-type dimers show the B-type dimerization dimerization is more plausible for Dio3. In silico protein-protein docking databases SymmDock and GalaxyRefineComplex were employed to successfully construct a Dio3 dimer based upon the B-type description. The refined Dio3 dimer was subject to MD simulations to test for the stability of the dimer. MMGBSA calculations show formation of the dimer is stable and interdimer interactions between the β-sheets and α-helices stabilize the dimer.


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