Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels

Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels

Bibliographic Details
Main Author: ZHANG, YANXIAN
Language:English
Published: University of Akron / OhioLINK 2021
Subjects:
Chemical Engineering
Amyloid inhibition
Cross-seeding
Hydrogel
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=akron1619525391595423
id ndltd-OhioLink-oai-etd.ohiolink.edu-akron1619525391595423
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Chemical Engineering
Amyloid inhibition
Cross-seeding
Hydrogel
spellingShingle Chemical Engineering
Amyloid inhibition
Cross-seeding
Hydrogel
ZHANG, YANXIAN
Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
author ZHANG, YANXIAN
author_facet ZHANG, YANXIAN
author_sort ZHANG, YANXIAN
title Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
title_short Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
title_full Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
title_fullStr Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
title_full_unstemmed Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels
title_sort molecular understanding and design of (i) amyloid inhibition and cross-seeding and (ii) functional, tough hydrogels
publisher University of Akron / OhioLINK
publishDate 2021
url http://rave.ohiolink.edu/etdc/view?acc_num=akron1619525391595423
work_keys_str_mv AT zhangyanxian molecularunderstandinganddesignofiamyloidinhibitionandcrossseedingandiifunctionaltoughhydrogels
_version_ 1719458249909993472
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-akron16195253915954232021-08-03T07:17:18Z Molecular Understanding and Design of (I) Amyloid Inhibition and Cross-seeding and (II) Functional, Tough Hydrogels ZHANG, YANXIAN Chemical Engineering Amyloid inhibition Cross-seeding Hydrogel Molecular understanding on various polymers, from naturally existing polymers (e.g., DNA, wool, silk, and other various proteins) to synthesized polymers are essential for bridging the gap between biological and synthetic systems. Amyloids are one of the representative natural polymers that formed through the polymerization of large number of monomeric peptides into long insoluble fibers. The aggregation and deposition of amyloids are considered as hallmark of various neurodegenerative diseases (i.e., protein-misfolded diseases, PMDs), including Alzheimer’s disease (AD, correlated with Aβ aggregation) and type II diabetes (T2D, correlated with hIAPP aggregation). In principle, any strategy to interfere with amyloid aggregation process is considered as potential pharmaceutical treatments for PMDs. However, the pathological pathway of amyloid aggregation is complicated and the possibility of cross-interaction between different amyloid peptides (also namely as “cross-seeding”) increased the difficulty to develop amyloid inhibition treatments. The lack of efficient treatments for PMDs and high failure rates of amyloid inhibitors make it imperative to obtain deeper understanding of amyloid structures, aggregation and develop practical inhibition strategies. Herein, we propose a new amyloid inhibition strategy to accelerate, instead of inhibiting, the aggregation process of amyloid peptides, and thus protect cells from aggregation-induced toxicity by quickly converting the most toxic oligomeric intermediates into less toxic fibrils. The natural compound, aromadendrin is discovered to possess dual promotion effect on both Aβ and hIAPP aggregation and exhibit dual inhibitory activity against the cytotoxicity of both Aβ and hIAPP. In another hand, compared with the well-studied homo-seeding aggregation, the cross-seeding is still a subject poorly explored and little is known about its sequence/structure-dependent aggregation mechanisms. Here, critical knowledge is developed to identify the molecular mechanism of cross-seeding. On the basis of potential pathological transmission between prion disease, AD, and T2D, we demonstrate GNNQQNY as a dual cross-seeding peptide to promote amyloid fibrillization of both Aβ and hIAPP via steric zipper interactions. Molecular dynamics (MD) simulations further support our steric zipper driven cross-seeding hypothesis, illustrate a structural basis for amyloid cross-seeding via non-covalent steric zipper interactions. Development of mechanically tough and functional hydrogels is essential to construct smart devices for better mimicking living organisms. To this end, a functional hydrogel with colorimetric response to force-, heat-, and light-stimuli is developed by introducing hydrophobic mechanophore (spiropyran) as cross-linker into the hydrophilic hydrogels system, through a unique micellar-polymerization method. With the presence of micellar network structures and the dynamically reversible mechanophore cross-linker, the hydrogel exhibits mechanical strong and self-recovery properties, together contribute to the application as strain sensor to repeatedly monitor color change under stretching and relaxing processes. Furthermore, a fully physically crosslinked hydrogel was developed for high toughness both in bulk and at interface, with excellent reversibility. The study reveals the structural basis for high mechanical strength of hydrogels, which contributes to both bulk and interfacial toughness with cooperative hydrogen bonds. The efforts on developing functional and tough hydrogels are promising for applications of hydrogels as smart and biocompatible sensors/devices. 2021-04-28 English text University of Akron / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=akron1619525391595423 http://rave.ohiolink.edu/etdc/view?acc_num=akron1619525391595423 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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