This work discusses applications of computational simulations to enzymatic systems with a particular focus on the effects of various small perturbations on cancer and disease-related systems. First, we cover the development of carbohydrate-based PET imaging ligands for Galectin-3, which is a protein overexpressed in pancreatic cancer tumors. We uncover several structural features for the ligands that can be used to improve their binding and efficacy.
Second, we discuss the AlkB family of enzymes. AlkB is the E. coli DNA repair protein for alkylation damage, and has human homologues with slightly different functions and substrates. Each has a conserved active site with a catalytic iron and a coordinating His...His...Asp triad. We have applied molecular dynamics (MD) to investigate the effect of a novel single nucleotide polymorphism for AlkBH7, which is correlated with prostate cancer and has an unknown function. We show that the mutation leads to active site distortion, which has been confirmed by experiments.
Thirdly, we investigate the unfolding of hen egg white lysozyme in 90% ethanol solution and low pH, to show the initial steps of unfolding from a native-like state to the disease-associated beta-sheet structure. We compare to mass spectrometry experiments and also show differing pathways based on protonation state. Finally, we discuss three different DNA polymerase systems. DNA polymerases are the primary proteins that replicate DNA during cell division, and have various extra or specific functions. We look at a proofreading-deficient DNA polymerase III mutant, the effects of solvent on DNA polymerase IV's ability to bypass bulky DNA adducts, and a variety of mutations on DNA polymerase kappa.
| Identifer | oai:union.ndltd.org:unt.edu/info:ark/67531/metadc1157647 |
| Date | 05 1900 |
| Creators | Walker, Alice Rachel |
| Contributors | Cisneros, Gerardo Andrés, Schwartz, Martin, Cundari, Thomas R., Liu, Jin, Schlegel, Bernhard |
| Publisher | University of North Texas |
| Source Sets | University of North Texas |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Format | xvi, 168 pages, Text |
| Rights | Public, Walker, Alice Rachel, Copyright, Copyright is held by the author, unless otherwise noted. All rights Reserved. |
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