A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

Abstract

The aggregation properties of two Ala-based pentapeptides were investigated by spectroscopic techniques and molecular dynamics (MD) simulations. The two peptides, both functionalized at the N-terminus with a pyrenyl group, differ in the insertion of an a-aminoisobutyric acid residue at position 4. We showed that this single modification of the homo-peptide sequence inhibits the aggregation of the pentapeptide in aqueous solutions. Atomic force microscopy imaging revealed that the two peptides form mesoscopic aggregates of very different morphologies when deposited on mica. MD experiments showed that the two peptides have a very different propensity to form b-pleated sheet structures, as confirmed by our spectroscopic measurements. The implications of these findings for our understanding of the mechanism leading to the formation of amyloid structures, primary responsible for numerous neurodegenerative diseases, are also discussed.

Controlling the Formation of Peptide Films: Fully Developed Helical Peptides are Required to Obtain a Homogenous Coating over a Large Area

“…In the self‐assembly of TrGA, hydrophobic effects predominate over the 3D‐structuring effects. Globular structures are observed independently of the hydrophobic or hydrophilic nature of the substrate and of the surface pressure applied for LB deposition …”

Aggregation propensity of Aib homo‐peptides of different length: an insight from molecular dynamics simulations

“…Multiple time decays have already been observed for excimers in organic polymeric glasses, where the short‐time decay components have been associated to the blueshifted region of the emission band and the long‐time tail to the redshifted region of the spectrum . The former is characteristic of a sandwich‐like arrangement of the aromatic moieties (H aggregates), whereas the relaxed (redshifted) component of the emission spectrum is usually assigned to parallel slipped‐out stacked chromophores (J‐aggregates) . The number and width of the lifetime distributions testify on the number of different conformers, the heterogeneity of the local environment embedding the fluorophore, and the number of fluorescent species.…”

Tuning the Morphology of Nanostructured Peptide Films by the Introduction of a Secondary Structure Conformational Constraint: A Case Study of Hierarchical Self-Assembly

“…The synthesis and characterization of the two pentapeptide analogs investigated, denoted in the following as PyA5 and PyA3UA, have already been published elsewhere. 19 Fourier-transform infrared (FTIR) absorption spectra of peptide films obtained by LB deposition were measured on a Thermo Fisher iS50 spectrophotometer (Thermo Fisher Scientific Co., Madison, WI) in the attenuated total reflection (ATR) mode using a ZnSe cell. Each spectrum was recorded mediating over 128 scans with a resolution of 2 cm -1 .…”

“…[16][17][18] We recently proved that a single Aib substitution at position 4 of an -(L-Ala)n-homo-pentapeptide strongly altered its conformational landscape and the morphology of the aggregates formed in aqueous solutions. 19 A 2-pyrenyl (Py) group, functionalizing both peptides at their N-terminus, was added to the peptide chain to investigate the role of an aromatic moiety in promoting peptide aggregation and to serve as an intrinsic fluorescent probe. We were able to show that aggregation in methanol/water solutions was mainly driven by the hydrophobic effect, but that the morphology of the mesoscopic peptide aggregates strongly depended on the secondary structure attained by the peptide building blocks.…”