Modeling intrinsically disordered proteins ; a comprehensive study of [alpha]-synuclein

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2015

Author dc:creator

• Ullman, Orly

Advisor dc:contributor.advisor

• Collin M. Stultz.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/97985

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/97985