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.