Date of Award

Spring 5-1-2024

Degree Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Donald Hamelberg


Protein dynamics play a key role in biological systems. When a protein performs its function, it goes through different conformational changes. Conformational changes orchestrate allosteric mechanisms that are involved in regulating various proteins' activity. Allostery has been a point of interest to understand protein function and design therapeutics. Allosteric drugs are under investigation as an alternative in case orthosteric drugs have high side effects. The allosteric effectors of proteins are of interest in cancer research. Cyclophilins are peptidyl-prolyl cis-trans isomerases (PPIases). PPIases are involved in protein folding, signal transduction, viral proliferation, oncogenesis, and protein regulation. Cyclophilin D is one type of the 17 cyclophilin isoforms. Cyclophilin D is localized in mitochondria and is involved in the regulation of mitochondrial pore opening, a process that is not well understood. Although cyclophilin isoforms share key conserved residues and structural properties, their activities and cellular locations slightly differ. With respect to p53, it is a tumor suppressor protein that is involved in many cancers when it is mutated. P53 is one of the proteins that is regulated by cyclophilin D in mitochondria. Pyruvate kinase is involved in glycolysis, a process that produces energy for the cell to survive. Our studies investigate the allosteric mechanism involved in the activity of Cyclophilin D, p53, and Pyruvate kinase. We used molecular dynamics to simulate the dynamics of the proteins. Post-molecular dynamics analysis such as energy calculations, residue-residue contact analysis, and path analysis were thereafter used to understand thermodynamic and allosteric mechanisms. Our results indicate the residues that are involved in the allosteric signal transmission. We have elucidated allosteric mechanisms and effects involved in systems of cis-trans isomerization by cyclophilins, especially Cyclophilin D and modified Cyclophilin D (post-translational modification). Finally, the regulation of Pyruvate kinase activation/inhibition was also elucidated.


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