Monomeric Polyglutamine Structures That Evolve into Fibrils

David Punihaole, Ryan S. Jakubek, Riley Workman, Lauren E. Marbella, Patricia Campbell, Jeffry D. Madura, Sanford A. Asher

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We investigate the solution and fibril conformations and structural transitions of the polyglutamine (polyQ) peptide, D2Q10K2 (Q10), by synergistically using UV resonance Raman (UVRR) spectroscopy and molecular dynamics (MD) simulations. We show that Q10 adopts two distinct, monomeric solution conformational states: a collapsed β-strand and a PPII-like structure that do not readily interconvert. This clearly indicates a high activation barrier in solution that prevents equilibration between these structures. Using metadynamics, we explore the conformational energy landscape of Q10 to investigate the physical origins of this high activation barrier. We develop new insights into the conformations and hydrogen bonding environments of the glutamine side chains in the PPII and β-strand-like conformations in solution. We also use the secondary structure-inducing cosolvent, acetonitrile, to investigate the conformations present in low dielectric constant solutions with decreased solvent-peptide hydrogen bonding. As the mole fraction of acetonitrile increases, Q10 converts from PPII-like structures into α-helix-like structures and β-sheet aggregates. Electron microscopy indicates that the aggregates prepared from these acetonitrile-rich solutions show morphologies similar to our previously observed polyQ fibrils. These aggregates redissolve upon the addition of water! These are the first examples of reversible fibril formation. Our monomeric Q10 peptides clearly sample broad regions of their available conformational energy landscape. The work here develops molecular-level insight into monomeric Q10 conformations and investigates the activation barriers between different monomer states and their evolution into fibrils. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)5953-5967
Number of pages15
JournalJournal of Physical Chemistry B
Volume121
Issue number24
DOIs
StatePublished - Jun 22 2017
Externally publishedYes

Fingerprint

Conformations
Acetonitrile
Peptides
acetonitrile
peptides
Chemical activation
activation
Hydrogen Bonding
strands
Hydrogen bonds
glutamine
Raman Spectrum Analysis
hydrogen
Molecular Dynamics Simulation
Glutamine
helices
Electron microscopy
Raman spectroscopy
Molecular dynamics
polyglutamine

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Punihaole, D., Jakubek, R. S., Workman, R., Marbella, L. E., Campbell, P., Madura, J. D., & Asher, S. A. (2017). Monomeric Polyglutamine Structures That Evolve into Fibrils. Journal of Physical Chemistry B, 121(24), 5953-5967. https://doi.org/10.1021/acs.jpcb.7b04060

Monomeric Polyglutamine Structures That Evolve into Fibrils. / Punihaole, David; Jakubek, Ryan S.; Workman, Riley; Marbella, Lauren E.; Campbell, Patricia; Madura, Jeffry D.; Asher, Sanford A.

In: Journal of Physical Chemistry B, Vol. 121, No. 24, 22.06.2017, p. 5953-5967.

Research output: Contribution to journalArticle

Punihaole, D, Jakubek, RS, Workman, R, Marbella, LE, Campbell, P, Madura, JD & Asher, SA 2017, 'Monomeric Polyglutamine Structures That Evolve into Fibrils', Journal of Physical Chemistry B, vol. 121, no. 24, pp. 5953-5967. https://doi.org/10.1021/acs.jpcb.7b04060
Punihaole D, Jakubek RS, Workman R, Marbella LE, Campbell P, Madura JD et al. Monomeric Polyglutamine Structures That Evolve into Fibrils. Journal of Physical Chemistry B. 2017 Jun 22;121(24):5953-5967. https://doi.org/10.1021/acs.jpcb.7b04060
Punihaole, David ; Jakubek, Ryan S. ; Workman, Riley ; Marbella, Lauren E. ; Campbell, Patricia ; Madura, Jeffry D. ; Asher, Sanford A. / Monomeric Polyglutamine Structures That Evolve into Fibrils. In: Journal of Physical Chemistry B. 2017 ; Vol. 121, No. 24. pp. 5953-5967.
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