Monomeric Polyglutamine Structures That Evolve into Fibrils

The Journal of Physical Chemistry. B
David PunihaoleSanford A Asher

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-ric...Continue Reading

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Citations

Aug 15, 2018·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Svetlana PylaevaDaniel Sebastiani
Jun 1, 2018·Trends in Analytical Chemistry : TRAC·Ryan S JakubekIgor K Lednev
Feb 6, 2019·The Journal of Physical Chemistry. B·Ryan S JakubekSanford A Asher
Apr 23, 2019·The Journal of Physical Chemistry. B·Ryan S JakubekSanford A Asher
Mar 24, 2018·The Journal of Physical Chemistry Letters·David PunihaoleSanford A Asher

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