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Issue 33, 2020
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Formation of peptide-based oligomers in dimethylsulfoxide: identifying the precursor of fibril formation

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Abstract

The well-studied dipeptide fluorenylmethyloxycarbonyl-di-phenylalanine (FmocFF) forms a rigid hydrogel upon dissolving in dimethylsulfoxide (DMSO) and dilution in H2O. Here, we explored the pre-aggregation of the peptide in pure DMSO by vibrational spectroscopies, X-ray powder diffraction and dynamic light scattering. Our results show an equilibrium between a dominant population of amorphous oligomers (on a length scale of 2 nm) and a small number of protofibrils/fibrils (on a length scale of 30 nm in the centimolar and of 200 nm in the sub-molar region). To probe the mechanism underlying the formation of these protofilaments, we measured the 1H-NMR, IR and visible Raman spectra of DMSO containing different FmocFF concentrations, ranging between 10 and 300 mM. Our data reveal that interpeptide hydrogen bonding leads to the self-assembly of FmocFF in the centimolar region, while π–π stacking between Fmoc-groups is observed above 100 mM. The high 3J(HNH) coupling constant of the N-terminal amide proton indicates that the Fmoc end-cap of the peptide locks the N-terminal residue into a conformational ensemble centered at a ϕ-value of ca. −120°, which corresponds to a parallel β-sheet type conformation. The 3J(HNH) coupling constant of the C-terminal residue is indicative of a polyproline II (pPII)/βt mixture. Our results suggest that the gelation of FmocFF caused by the addition of a small amount of water to DMSO mixtures is facilitated by the formation of disordered protofibrils in pure DMSO.

Graphical abstract: Formation of peptide-based oligomers in dimethylsulfoxide: identifying the precursor of fibril formation

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Supplementary files

Article information


Submitted
06 Jan 2020
Accepted
09 Jul 2020
First published
30 Jul 2020

Soft Matter, 2020,16, 7860-7868
Article type
Paper

Formation of peptide-based oligomers in dimethylsulfoxide: identifying the precursor of fibril formation

M. S. Levine, M. Ghosh, M. Hesser, N. Hennessy, D. M. DiGuiseppi, L. Adler-Abramovich and R. Schweitzer-Stenner, Soft Matter, 2020, 16, 7860
DOI: 10.1039/D0SM00035C

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