Modeling intrinsically disordered proteins ; a comprehensive study of [alpha]-synuclein
Author(s)
Ullman, Orly
DownloadFull printable version (13.80Mb)
Other Contributors
Massachusetts Institute of Technology. Department of Chemistry.
Advisor
Collin M. Stultz.
Terms of use
Metadata
Show full item recordAbstract
Parkinson's disease (PD) affects over 10 million people worldwide and has no cure. Moreover, current treatments for PD have limited efficacy. Studies that advance our understanding of the mechanism of neurodegeneration in PD will provide guidance in our search for effective therapies for this neurodegenerative disorder. PD is characterized clinically by motor deficits - namely resting tremors, rigidity, bradykinesia and postural instability - and pathologically by intraneuronal inclusions in the substantia nigra. Several studies suggest that a-synuclein, the major component of these intracellular inclusions, plays a major role in the neurodegenerative process. Therefore understanding the structural properties of [alpha]-synuclein and its aggregation mechanism is of particular interest. [alpha]-synuclein is particularly challenging to study because it is an Intrinsically Disordered Protein (IDP); i.e., it lacks a well-defined structure in aqueous solution. Unlike folded proteins, IDPs typically interconvert between many different conformations during their biological lifetime. In this thesis we apply novel methods to develop models for IDPs and apply them to asynuclein. The overriding hypothesis that forms the basis of this work is that IDPs in solution can be modeled as a finite set of energetically favorable structures, where each structure corresponds to an energy minimum on a complex energy landscape. The number of structures in the resulting ensemble is related to the resolution in which one wishes to view the energy landscape of the protein. We demonstrate that this approach leads to new insights into the aggregation mechanism of [alpha]-synuclein.
Description
Thesis: Ph. D. in Physical Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2015. Cataloged from PDF version of thesis. In title on title page, "[alpha]" appears as lower case Greek letters. Vita. Includes bibliographical references (pages 91-104).
Date issued
2015Department
Massachusetts Institute of Technology. Department of ChemistryPublisher
Massachusetts Institute of Technology
Keywords
Chemistry.