Atomic Insight on Inhibition of Fibrillization of Dipeptides by Replacement of Phenylalanine with Tryptophan

Abstract

Tryptophan (Trp) conjugates destabilize amyloid fibrils responsible for amyloidoses. However, the mechanism of such destabilization is obscure. Herein the self-assembly of four synthesized Trp-containing dipeptides Boc-xxx-Trp-OMe (xxx: Val, Leu, Ile, and Phe) has been investigated and compared with the existing report on their Phe congeners. Two among them are the C-terminal tryptophan analogs of Boc-Val-Phe-OMe (VF, Aβ18–19) and Boc-Phe-Phe-OMe (FF, Aβ19–20), part of the central hydrophobic region of amyloid-β (Aβ1–42). While Boc-Val-Trp-OMe (VW), Boc-Leu-Trp-OMe (LW), Boc-Ile-Trp-OMe (IW), and Boc-Phe-Trp-OMe (FW) displayed a spherical morphology in FESEM and AFM images, the corresponding phenylalanine-containing dipeptides displayed various fibrous structures. Single-crystal X-ray diffraction (SC-XRD) indicated that peptides VW and IW exhibited structures containing parallel β-sheet, cross-β-structure, sheet-like layer structure, and helical arrangement in the solid state. Interestingly, peptide FW displayed inverse γ-turn conformation (similar to open-turn structure), antiparallel β-sheet structure, columnar structure, supramolecular nanozipper structure, sheet-like layer arrangement, and helical architecture in the solid state. The open-turn conformation and nanozipper structure formation by FW may be the first example of a dipeptide that forms such structures. The minute but consistent differences in molecular packing at the atomic level between Trp and Phe congeners may be responsible for their remarkably different supramolecular structure generation. This molecular-level structural analysis may be helpful for the de novo design of peptide nanostructures and therapeutics. Similar studies by the Debasish Haldar group are reported, but they investigated the inhibition of fibrillization of dipeptides by tyrosine and interactions are expectedly different.

Structural Transformation of Coassembled Fmoc-Protected Aromatic Amino Acids to Nanoparticles

“…The lack of these essential interactions also caused the assembly process to remain at the intermediate spherical nanoparticle stage. Indeed, some recent studies revealed that the tryptophan residue could act as a fiber structure inhibitor, converting many fiber-like structures into nanoparticles when the tryptophan residue was introduced into the peptide sequences. − For example, it was reported that a special motif called tryptophan zipper generated by cross-standing pairing of indole rings played an important role in retarding nanofiber formation, leading to the formation of nanoparticles . These studies support why we hypothesize that the INP stage was locked by Fmoc-Trp-OH in our binary assembly system.…”

Influence of Chirality on the Self-Assembly of Dipeptides and Sensing of Fe3+

“…Molecular self-assembly is a procedure for creating ensembles of nanostructures, where molecules autonomously assemble through diverse noncovalent interactions (van der Waals, electrostatic, H-bonding, π–π stacking, and hydrophobic interactions). − Supramolecular self-assembly based on small peptides creates significant interest because of chemical diversity, cost-effectiveness, and convenient modulations compared to other molecules . Peptide self-assembly offers various nanostructures − including nanowires, nanofibrils, , nanoribbons, nanospheres, nanotapes, nanobelts, nanovesicle, and nanotubes depending on the internal and external forces. Peptide nanostructures typically exhibit good biocompatibility, low toxicity, low immunogenicity, biodegradability, and target specificity. − Consequently, they find widespread applications in drug delivery, tissue engineering, biomedical, cell culture, nanoelectronics, and sensors .…”