Polyglutamine Fibrils: New Insights into Antiparallel β-Sheet Conformational Preference and Side Chain Structure

David Punihaole, Riley J. Workman, Zhenmin Hong, Jeffry D. Madura, Sanford A. Asher

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Understanding the structure of polyglutamine (polyQ) amyloid-like fibril aggregates is crucial to gaining insights into the etiology of at least ten neurodegenerative disorders, including Huntington's disease. Here, we determine the structure of D2Q10K2 (Q10) fibrils using ultraviolet resonance Raman (UVRR) spectroscopy and molecular dynamics (MD). Using UVRR, we determine the fibril peptide backbone Ψ and glutamine (Gln) side chain X3 dihedral angles. We find that most of the fibril peptide bonds adopt antiparallel β-sheet conformations; however, a small population of peptide bonds exist in parallel β-sheet structures. Using MD, we simulate three different potential fibril structural models that consist of either β-strands or β-hairpins. Comparing the experimentally measured Ψ and X3 angle distributions to those obtained from the MD simulated models, we conclude that the basic structural motif of Q10 fibrils is an extended β-strand structure. Importantly, we determine from our MD simulations that Q10 fibril antiparallel β-sheets are thermodynamically more stable than parallel β-sheets. This accounts for why polyQ fibrils preferentially adopt antiparallel β-sheet conformations instead of in-register parallel β-sheets like most amyloidogenic peptides. In addition, we directly determine, for the first time, the structures of Gln side chains. Our structural data give new insights into the role that the Gln side chains play in the stabilization of polyQ fibrils. Finally, our work demonstrates the synergistic power and utility of combining UVRR measurements and MD modeling to determine the structure of amyloid-like fibrils. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)3012-3026
Number of pages15
JournalJournal of Physical Chemistry B
Issue number12
StatePublished - Mar 31 2016

Bibliographical note

Funding Information:
Funding for this work was provided by the University of Pittsburgh (D.P., Z.H., S.A.A.) and partially supported by NIH R01 DA027806 (J.D.M. and R.J.W.). The MD simulation computer time was supported by XSEDE MCB060069, and computer equipment was purchased from NSF funds (CHE-1126465 and P116Z080180). The DFT calculations were supported by the University of Pittsburgh Center for Simulation and Modeling through the supercomputing resources provided. We thank Dr. Sergei V. Bykov, Liqi Feng, Jonathan Weisberg, and Jonathan Wert for useful discussions. We are also grateful to Dr. Steven Geib and Dr. Alexander Makhov for technical assistance with the X-ray diffraction measurements and electron microscopy, respectively.

Publisher Copyright:
© 2016 American Chemical Society.


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