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Molecular Structural Insights of Polyglutamine-Rich Amyloid-like Fibrils Using UV Resonance Raman Spectroscopy

Punihaole, David (2016) Molecular Structural Insights of Polyglutamine-Rich Amyloid-like Fibrils Using UV Resonance Raman Spectroscopy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

There is currently little that is known about the structure of polyglutamine (polyQ) fibrils, which are involved in at least ten neurodegenerative diseases, including Huntington's. Given the difficulty of studying these aggregates, new and incisive biophysical methods need to be developed in order to obtain high-resolution structural information of polyQ and other amyloid-like fibrils. Here, we present our recent advances in UV resonance Raman (UVRR) spectroscopy that enable the elucidation of molecular-level structural information of amyloid-like fibrils. We show, for example, how the primary amide UVRR bands report on the local hydrogen bonding and dielectric environment of glutamine side chains. We also discuss a newly discovered spectroscopic marker, the Amide III$^{\textrm{P}}$ vibration, which sensitively reports on the OCCC dihedral angle of glutamine (Gln) and asparagine (Asn) side chains. These and other spectroscopic markers are used to gain insights into the peptide backbone and side chain structures of polyQ peptides in solution-state and in fibrils. Finally, we demonstrate how the structural information obtained from UVRR can be utilized to guide Molecular Dynamics simulations in order to obtain experimentally validated structural models of polyQ fibrils.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Punihaole, Daviddap54@pitt.eduDAP54
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAsher, Sanford A.asher@pitt.eduASHER
Committee MemberJen-Jacobson, Lindaljen@pitt.eduLJEN
Committee MemberWetzel, Ronaldrwetzel@pitt.eduRWETZEL
Committee MemberSaxena, Sunilsksaxena@pitt.eduSKSAXENA
Committee MemberGarrett-Roe, Seansgr@pitt.eduSGR
Date: 3 October 2016
Date Type: Publication
Defense Date: 13 July 2016
Approval Date: 3 October 2016
Submission Date: 8 June 2016
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 209
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Molecular Biophysics and Structural Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: none
Date Deposited: 03 Oct 2016 14:17
Last Modified: 15 Nov 2016 14:33
URI: http://d-scholarship.pitt.edu/id/eprint/28138

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