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Protein folding and amyloid formation in various environments

dc.contributor.advisorThirumalai, Devarajanen_US
dc.contributor.advisorBrooks, Bernarden_US
dc.contributor.authorO'Brien, Edward Patricken_US
dc.date.accessioned2009-01-24T07:07:36Z
dc.date.available2009-01-24T07:07:36Z
dc.date.issued2008-11-21en_US
dc.identifier.urihttp://hdl.handle.net/1903/8810
dc.description.abstractUnderstanding and predicting the effect of various environments that differ in terms of pH and the presence of cosolutes and macromolecules on protein properties is a formidable challenge. Yet this knowledge is crucial in understanding the effect of cellular environments on a protein. By combining thermodynamic theories of solution condition effects with statistical mechanics and computer simulations we develop a molecular perspective of protein folding and amyloid formation that was previously unobtainable. The resulting Molecular Transfer Model offers, in some instances, quantitatively accurate predictions of cosolute and pH effects on various protein properties. We show that protein denatured state properties can change significantly with osmolyte concentration, and that residual structure can persist at high denaturant concentrations. We study the single molecule mechanical unfolding of proteins at various pH values and varying osmolyte and denaturant concentrations. We find that the the effect of varying solution conditions on a protein under tension can be understood and qualitatively predicted based on knowledge of that protein's behavior in the absence of force. We test the accuracy of FRET inferred denatured state properties and find that currently, only qualitative estimates of denatured state properties can be obtained with these experimental methods. We also explore the factors governing helix formation in peptides confined to carbon nanotubes. We find that the interplay of the peptide's sequence and dimensions, the nanotube's diameter, hydrophobicity and chemical heterogeneity, lead to a rich diversity of behavior in helix formation. We determine the structural and thermodynamic basis for the dock-lock mechanism of peptide deposition to a mature amyloid fibril. We find multiple basins of attraction on the free energy surface associated with structural transitions of the adding monomer. The models we introduce offer a better understanding of protein folding and amyloid formation in various environments and take us closer to understanding and predicting how the complex environment of the cell can effect protein properties.en_US
dc.format.extent14748866 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.titleProtein folding and amyloid formation in various environmentsen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentChemical Physicsen_US
dc.subject.pqcontrolledBiophysics, Generalen_US
dc.subject.pqcontrolledChemistry, Physicalen_US
dc.subject.pqcontrolledPhysics, Condensed Matteren_US
dc.subject.pquncontrolledprotein foldingen_US
dc.subject.pquncontrolledsingle moleculeen_US
dc.subject.pquncontrolledureaen_US
dc.subject.pquncontrolledpHen_US
dc.subject.pquncontrolledthermodynamicsen_US
dc.subject.pquncontrolledhelixen_US


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