Cationic polymethacrylate-copolymer acts as an agonist for beta-amyloid and antagonist for amylin fibrillation

Abstract

In human, amyloid-beta (A{beta}) and islet amyloid polypeptide (hIAPP) aggregations are linked to Alzheimers disease and Type-2 Diabetes, respectively. There is significant interest in better understanding the aggregation process by using chemical tools. Here, we show the ability of a cationic polymethacrylate-copolymer (PMAQA) to quickly induce {beta}-hairpin structure and promote fibrillation in A{beta}40, and to constrain the conformational plasticity of hIAPP for several days and inhibit its aggregation at sub-micromolar concentrations. NMR experiments and atomistic molecular dynamics simulations reveal that PMAQA electrostatically interacts with A{beta}40s Glu22 and Asp23 followed by {beta}-sheet induction while it binds strongly to the closest proximity of amyloid core domain (NFGAIL) of hIAPP and restrain its structural rearrangement. This study provides a valuable approach to develop polymer-based anti-amyloid inhibitors that may diminish the population of intermediates of A{beta}40 or hIAPP.