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Probing The Early Stages Of Polyglutamine Aggregation With Computational Methods, Andreas Vitalis
Probing The Early Stages Of Polyglutamine Aggregation With Computational Methods, Andreas Vitalis
All Theses and Dissertations (ETDs)
Exonic CAG repeat diseases are a class of neurodegenerative age-of-onset diseases caused by an unstable trinucleotide expansion in a coding region of a gene. The most prominent example is Huntington's disease: HD) whose symptoms are characterized by loss of motor control and cognitive deficits. For all nine of the known CAG repeat diseases, pathology is ascribed to the mutant proteins which carry expanded stretches of glutamine residues: polyglutamine). The length of the polyglutamine segment is inversely correlated with the disease age-of-onset. Protein aggregates are routinely found in postmortem tissue samples of brains of HD patients. These findings suggest a prominent …
Advances In Computational Solvation Thermodynamics, Matthew Wyczalkowski
Advances In Computational Solvation Thermodynamics, Matthew Wyczalkowski
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The aim of this thesis is to develop improved methods for calculating the free energy, entropy and enthalpy of solvation from molecular simulations. Solvation thermodynamics of model compounds provides quantitative measurements used to analyze the stability of protein conformations in aqueous milieus. Solvation free energies govern the favorability of the solvation process, while entropy and enthalpy decompositions give insight into the molecular mechanisms by which the process occurs. Computationally, a coupling parameter λ modulates solute-solvent interactions to simulate an insertion process, and multiple lengthy simulations at a fixed λ value are typically required for free energy calculations to converge; entropy …
Computational And Experimental Investigation Of Allosteric Communication In The Transcriptional Regulator Nikr, Michael Bradley
Computational And Experimental Investigation Of Allosteric Communication In The Transcriptional Regulator Nikr, Michael Bradley
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The Ni2+ and DNA binding protein NikR is involved in nickel regulation in Escherichia coli through transcriptional repression of the NikABCDE nickel permease. NikR is a homotetramer and each chain contains both a DNA binding ribbon-helix-helix: RHH) domain and a Ni2+ binding regulatory ACT: aspartokinase, chorismate mutase, TyrA) fold. Work herein combines computational modeling of NikR structure with experimental studies aimed at understanding allosteric communication between the ACT and RHH domains. Hydrogen/deuterium exchange mass spectrometry shows a Ni2+ specific NikR conformational change relative to bound Cu2+, Co2+, and Zn2+. Concurrent coordination geometry and in vivo repressor function studies show that …