Crystallographic insights into the self‐assembly of KLVFF amyloid‐beta peptides

Abstract

Amyloidogenic peptide fragment KLVFF (H N-Lys-Leu-Val-Phe-Phe-COOH, Aβ ), the core-sequence of the polypeptide Aβ40, is a well-studied model for amyloid formation. However, due to its low crystallinity, detailed atomic information of KLVFF structure is lacking. Here we report the high-resolution single-crystal X-ray structure of two monohalogenated KLVFF derivatives, KLVFF(I) and KLVFF(Br). The obtained results highlight how halogenation is a good strategy to promote crystallization and facilitate the phase determination of KLVFF(I) and KLVFF(Br) fragments. Detailed structural studies on the packing features of both monohalogenated derivatives reveal the role of the halogen atoms showing that when they are positioned on the Phe aromatic moiety at the C-terminus they do not form halogen bonds and thus do not produce any extra stabilization of the β-sheet in the self-assembly process. The structural evidences gained from these studies corroborate the various polymorphic nanostructures of the halogenated variants of KLVFF and confirm the possibility to use halogenation as innovative strategy to tune the morphology of this pentapeptide.

Halogen bonding as a key interaction in the self‐assembly of iodinated diphenylalanine peptides

“…The second is a peptide having a single iodine atom on the aromatic residue at the N‐terminus—F(I)F—(Figure ). Mono‐iodination on the C‐terminus—FF(I)—was not studied, since halogenation in this position was proved to do not have an active role in the self‐assembly, as demonstrated by the crystal structure of KLVFF(I) …”

“…Recent works from our group reported the impact of halogenation in the self‐assembly properties of simple organic systems containing phenylalanine residues. Studies based both on a single phenylalanine and short peptide sequences confirmed that halogenation enhances the self‐aggregating propensity compared to the corresponding nonhalogenated systems, this proclivity being a function of halogen polarizability. Moreover, in the case of amyloid peptide fragments, several kinds of nanostructures were observed by changing number, position, and nature of the halogen substitution .…”

Linear Chimeric Triblock Molecules Self‐Assembled Micelles with Controllably Transformable Property to Enhance Tumor Retention for Chemo‐Photodynamic Therapy of Breast Cancer

“…This problem can be resolved better by nanomedicines staying in shape one, such as spheres, to circulate and distribute in the body, and transforming into another shape, such as fibers, to facilitate the retention inside tumor. Phe‐Phe‐Val‐Leu‐Lys (FFVLK) peptide, derived from β‐amyloid, tends to form a β‐sheet structure relying on extensive intermolecular hydrogen bonds that enable fibers formation . However, after introducing hydrophobic heads and hydrophilic tail in FFVLK peptide, the resultant linear chimeric molecules form micelles when rapidly dissolved in aqueous solvents.…”

Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

“…Halogenation of the C-terminus was not included as it was previously shown not to affect the self-assembly of the parent amyloid sequence Lys-Leu-Val-Phe-Phe. 30 Iodination in the ortho- or meta-positions of Phe was not studied as it was envisaged to likely disrupt assembly due to iodine’s bulky nature and ability to engage in halogen bonding with carbonyl groups. 30 Our choice of heterochiral sequences was dictated by the observation that introducing d -amino acids at selected positions has proven successful as a strategy to achieve hydrogels from uncapped tripeptides.…”