In Situ Molecular-Level
Insights into the Interfacial
Structure Changes of Membrane-Associated Prion Protein Fragment [118–135]
Investigated by Sum Frequency Generation Vibrational Spectroscopy
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Abstract
Protein aggregation is associated with many “protein
deposition
diseases”. A precise molecular detail of the conformational
transitions of such a membrane-associated protein structure is critical
to understand the disease mechanism and develop effective treatments.
One potential model peptide for studying the mechanism of protein
deposition diseases is prion protein fragment [118–135] (PrP118–135),
which shares homology with the C-terminal domain of the Alzheimer’s
β-amyloid peptide. In this study, sum frequency generation vibrational
spectroscopy (SFG-VS) has been applied to characterize interactions
between PrP118–135 and 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phospho-(1′-<i>rac</i>-glycerol) (POPG)
lipid bilayer in situ. The conformation change and orientation of
PrP118–135 in lipid bilayers have been determined using SFG
spectra with different polarization combinations. It is found that
low-concentration PrP118–135 predominantly adopts α-helical
structure but with tiny β-sheet structure. With the PrP118–135
concentration increasing, the molecular number ratio of parallel β-sheet
structure increases and reaches about 44% at a concentration of 0.10 mg/mL,
indicating the formation of abnormally folded scrapie isoforms. The
α-helical structure inserts into the lipid bilayer with a tilt
angle of ∼32° versus the surface normal, while the β-sheet
structure lies down on the lipid bilayer with the tilt and twist angle
both of 90°. The 3300 cm<sup>–1</sup> N–H stretching
signal in psp spectra arises from α-helical structure at low
PrP concentration and from the β-sheet structure at high PrP
concentration. Results from this study will provide an in-depth insight
into the early events in the aggregation of PrP in cell membrane