Polymer-based nanodiscs are valuable tools in biomedical research that can offer a detergent-free solubilization of membrane proteins maintaining their native lipid environment. Here, we introduce a novel ~1.6 kDa SMA-based polymer with styrene:maleic acid moieties that can form nanodiscs containing a planar lipid bilayer which are useful to reconstitute membrane proteins for structural and functional studies. The physicochemical properties and the mechanism of formation of polymer-based nanodiscs are characterized by light scattering, NMR, FT-IR, and TEM imaging experiments. A remarkable feature is that nanodiscs of different sizes, from nanometer to sub micrometer diameter, can be produced only by varying the lipid-to-polymer ratio. As demonstrated, the small size nanodiscs (up to ~30 nm diameter) can be used for solution NMR studies whereas the magnetic-alignment of macro-nanodiscs (diameter of >~40 nm) can be exploited for solid-state NMR studies on membrane proteins.

Our knowledge of the molecular events underlying type 2 diabetes mellitus-a protein conformational disease characterized by the aggregation of islet amyloid polypeptide (IAPP) in pancreatic β cells-is limited. However, amyloid-mediated membrane damage is known to play a key role in IAPP cytotoxicity, and therefore the effects of lipid composition on modulating IAPP-membrane interactions have been the focus of intense research. In particular, membrane cholesterol content varies with aging and consequently with adverse environmental factors such as diet and lifestyle, but its role in the development of the disease is controversial. In this study, we employ a combination of experimental techniques and in silico molecular simulations to shed light on the role of cholesterol in IAPP aggregation and the related membrane disruption. We show that if anionic POPC/POPS vesicles are used as model membranes, cholesterol has a negligible effect on the kinetics of IAPP fibril growth on the surface of the bilayer. In addition, cholesterol inhibits membrane damage by amyloid-induced poration on membranes, but enhances leakage through fiber growth on the membrane surface. Conversely, if 1:2 DOPC/DPPC raft-like model membranes are used, cholesterol accelerates fiber growth. Next, it enhances pore formation and suppresses fiber growth on the membrane surface, leading to leakage. Our results highlight a twofold effect of cholesterol on the amyloidogenicity of IAPP and help explain its debated role in type 2 diabetes mellitus.

Polymer-based nanodiscs are valuable tools in biomedical researcht hat can offer ad etergent-free solubilization of membrane proteins maintaining their native lipid environment. Herein, we introduce anovel ca. 1.6 kDa SMAbased polymer with styrene:maleic acid moieties that can form nanodiscs containing aplanar lipid bilayer whichare useful to reconstitute membrane proteins for structural and functional studies.The physicochemical properties and the mechanism of formation of polymer-based nanodiscs are characterized by light scattering,NMR, FT-IR, and TEM. Aremarkable feature is that nanodiscs of different sizes,f rom nanometer to submicrometer diameter,can be produced by varying the lipid-topolymer ratio.T he small-sizen anodiscs (up to ca. 30 nm diameter) can be used for solution NMR spectroscopystudies whereas the magnetic-alignment of macro-nanodiscs (diameter of > ca. 40 nm) can be exploited for solid-state NMR studies on membrane proteins.

Polymer nanodisks have shown great potential as membrane mimetics that enable the study of functional membrane protein structural biology and also have a wider application in other fields such as drug delivery. To achieve these research goals, the ability to have a cheap, simple, fully customizable platform for future nanodisks technology applications is paramount. Here, a facile functionalization of polyacrylic acid (PAA) with varying hydrophobic groups that form nanodisks at different sizes is successfully demonstrated. The study shows that the choice of hydrophobic group can have a noticeable effect on the polymer solubilization properties and polymer‐induced perturbation to the encased lipid bilayer. Due to this robust, tunable chemical synthesis method, PAA is an exciting platform for the future optimization of the hydrophobic, hydrophilic, or direct purposed functionalizations for polymer nanodisks.