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Conformational Tuning of Amylin by Charged SMA Copolymers

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. Graphical abstract