Conformational Tuning of Amylin by Charged Styrene-maleic-acid Copolymers

Abstract

Human amylin is linked to type-2 diabetes and forms structurally heterogeneous amyloids that are pathologically relevant. Therefore, understanding the fundamental forces governing the formation of heterogeneous aggregates is important. Here, using derivatives (SMAQA + /SMAEA -) of styrene-maleic-acid (SMA) copolymer (~2.2kDa), we demonstrate the quick formation (~ in minutes) of amylin globulomers and fibers. High-speed AFM tracked the quick formation of de novo globular amylin oligomers and arrestment of fibrillation by SMAQA, whereas SMAEA accelerates amylin fibrillation. This observation is further supported by DOSY and STD NMR experiments. CD results show that SMAQA or SMAEA binding generates α-helix or β-sheet rich amylin structures, respectively. Atomistic insights are revealed by 2D NMR and microseconds all-atom MD simulation. Together, this study highlights the importance of charge-charge interaction in tuning the fibrillation pathways of amylin that could be of therapeutic interest.Supporting information for this article is given via a link at the end of the document

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…918 Recently, short anionic and cationic styrene-based copolymers (~2.2 kDa) are shown to catalyze IAPP aggregation by quickly inducing the formation of non-toxic fibers; whereas cationic styrene copolymers inhibit IAPP aggregation and induce generation of non-toxic globulomers. 919 Smith et al recently developed polymer-peptide conjugates to control the molecular ordering of Aβ structure and stability, but the pathological phenotypes of these nanostructure are yet to be tested.920 Thermoresponsive polymers varying in hydrophobicity/hydrophilicity ratio is shown to selectively modulate Aβ aggregation kinetics. 921 Poly(p-phenylene vinylene) derived polymer is shown to degrade Aβ fibers that are nontoxic and to clear the Aβ plaques from the brain tested ex vivo.…”

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

“…In this way, the consecutive imaging of fibril seeds adhered on the stage in advance and in the same observation area after the addition of monomers could not only observe fibril elongation immediately, but also distinguished between the original fibrils and the de novo fibrils by identifying the appearance time and place of the fibrils. The effects of styrene-maleic acid copolymers varying with charge (SMAEA/SMAQA) on amylin were investigated using HS-AFM [164]. The results from this study identified morphologically distinct amylin species.…”

“…The effects of styrene–maleic acid copolymers varying with charge (SMAEA/SMAQA) on amylin were investigated using HS-AFM [ 164 ]. The results from this study identified morphologically distinct amylin species.…”

On-Pathway Oligomer of Human Islet Amyloid Polypeptide Induced and Stabilized by Mechanical Rotation During MAS NMR

“…Previous work has demonstrated the ability of small molecules, peptides, lipid membranes, metals, synthetic polymers, pH, and electric fields to alter amyloid aggregation pathways and in some cases to stabilize oligomeric intermediates for further structural studies. [12][13][14][15][16][17][18][19][20][21][22][23][24] Here, we provide the first report, to our knowledge, of the ability of the mechanical forces associated with MAS to stabilize intermediate, onpathway aggregates of human islet amyloid polypeptide (hIAPP) in an aqueous environment.…”