Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host-Guest Chemistry

Abstract

Amyloid fibrils have recently been highlighted for their diverse applications as functional nanomaterials in modern chemistry. However, tight control to obtain a targeted fibril length with low heterogeneity has not been achieved because of the complicated nature of amyloid fibrillation. Herein, we demonstrate that fibril assemblies can be homogeneously manipulated with desired lengths from ~40 nm to ~10 μm by a phase transfer of amyloid proteins based on host-guest chemistry. We suggest that host-guest interactions with cucurbit[6]uril induce a phase transfer of amyloid proteins (human insulin, human islet amyloid polypeptide, hen egg lysozyme, and amyloid-β 1–40 & 1–42) from the soluble state to insoluble state when the amount of cucurbit[6]uril exceeds its solubility limit in solution. The phase transfer of the proteins kinetically delays the nucleation of amyloid proteins, while the nuclei formed in the early stage are homogeneously assembled to fibrils. Consequently, supramolecular assemblies of amyloid proteins with heterogeneous kinetics can be controlled by protein phase transfer based on host-guest interactions.

Kinetic Modulation of Amyloid-β (1–42) Aggregation and Toxicity by Structure-Based Rational Design

“…For example, the average fibril lengths of the 20%, 50%, and 100% T2 mutants were 386.3 ± 240.0, 495.5 ± 393.7, and 742.7 ± 774.9 nm, respectively. Compared to the fibril length of the WT (334.5 ± 218.2 nm), fibrils are longer and more broadly dispersed, indicating retarded nuclei formations . It appears that the mutants interacted with the WT, thereby delaying nucleation.…”

“…Compared to the fibril lengths of WT (334.5 ± 218.2 nm), the T3 and T4 mutants produced dramatically short fibrils (254.4 ± 142.2 and 199.3 ± 95.5 nm, respectively) with narrow dispersion. Because facilitated self-assembly can enhance the number density of nuclei, the system would contain shorter fibrils and the ThT intensities would be dramatically enhanced. , In contrast, the mutants that showed suppressed amyloid aggregation formed broadly dispersed, longer fibrils, indicating retarded early stage aggregation …”

Allosteric Signal-Amplification Sensing of Peptides with Cyclodextrin-Polymer Conjugates in Aqueous Media

“…This is because peptides are structurally and conformationally diverse molecules, which complicate the rational design and synthesis of chemosensors. − Nevertheless, several supramolecular hosts with various binding motives have been employed as chemosensors for peptides. For instance, cyclodextrins (CDx), − cucurbit­[ n ]­urils, − calix­[ n ]­arenes, , and self-assembled coordination cages , have been used as cyclic hosts. Moreover, molecular tweezers, , hydrogen-bonding receptors, − crown ether-spacer conjugates, , and Zn­(II)-complexed fluorophores , have been used as acyclic hosts.…”

Morphological Effects of CuO Nanostructures on Fibrillation of Human Serum Albumin

“…Consequently, inhibition or disturbance of this fibrillation process is regarded as one of the emergent propositions in the prevention of all amyloid-related diseases. In recent times, nanomaterial-modulated fibrillations of various amyloidogenic proteins have gained attention as they are found to play a pivotal role in promoting, hindering, or disintegrating the fibrillation process. − Nanomaterials are reported to have strong interactions with the protein monomers or growing oligomers leading to interference in the nucleation as well as in the elongation step , of the protein fibrillation process. Owing to the dimensional similarity of the nanomaterials with the protein molecules, they are also known to offer significant therapeutic potential by regulating the fibrillation process.…”